Materiały źródłowe

• #1 Down Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK526016/

  Down syndrome (trisomy 21) is a genetic disorder caused by the presence of all or a portion of a third chromosome 21. […] It is the presence of all or part of the third copy of chromosome 21 that causes Down syndrome, the most common chromosomal abnormality occurring in humans. […] The majority of patients with Down syndrome have an extra copy of chromosome 21. There are different hypotheses related to the genetic basis of Down syndrome and the association of different genotypes with the phenotypes. Among them is gene dosage imbalance, in which there is an increased dosage or number of genes of Hsa21, which results in increased gene expansion. […] The critical region hypothesis is also well-known in this list. Down syndrome critical regions (DSCR) are a few chromosomal regions that are associated with partial trisomy for Has21. DSCR on 21q21.22 is responsible for many clinical features of Down syndrome.

• #2 Down syndrome – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/down-syndrome/symptoms-causes/syc-20355977

  There are 23 pairs of chromosomes, for a total of 46. Half the chromosomes come from the egg and half come from the sperm. In Down syndrome, there is an additional copy of chromosome 21, resulting in three copies instead of the usual two copies. […] Down syndrome is a genetic condition caused when an unusual cell division results in an extra full or partial copy of chromosome 21. This extra genetic material causes the developmental changes and physical features of Down syndrome. […] Down syndrome results from an unusual cell division involving chromosome 21. This unusual cell division results in an extra partial or full chromosome 21. This extra genetic material changes how the body and brain develop. It is responsible for the physical features and developmental problems of Down syndrome.

• #3 Down Syndrome | Birth Defects | CDC

  https://www.cdc.gov/birth-defects/about/down-syndrome.html

  Down syndrome is a condition in which a person has an extra copy of chromosome 21. Chromosomes are small „packages” of genes in the body’s cells, which determine how the body forms and functions. […] When babies are growing, the extra chromosome changes how their body and brain develop. This can cause both physical and mental challenges. […] We do not know for sure why Down syndrome occurs or how many different factors play a role. We do know that some things can affect your risk of having a baby with Down syndrome. […] One factor is your age when you get pregnant. The risk of having a baby with Down syndrome increases with age. This is especially the case if you are 35 years or older when you get pregnant. […] However, the majority of babies with Down syndrome are still born to mothers less than 35 years old. This is because there are many more births among younger women. […] Parents with one child with Down syndrome have a higher chance of having another child with Down syndrome regardless of age.

• #4 Down syndrome – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/down-syndrome/symptoms-causes/syc-20355977

  Any one of three genetic changes can cause Down syndrome: […] Trisomy 21. About 95% of the time, Down syndrome is caused by trisomy 21. This means the person has three copies of chromosome 21, instead of the usual two copies. The extra chromosome 21 is in all cells in the body. Trisomy 21 results from an unusual cell division during the development of the sperm cell or the egg cell. […] Mosaic Down syndrome. This is a rare form of Down syndrome. People with mosaic Down syndrome have only some cells with an extra copy of chromosome 21. This mosaic of typical and changed cells is caused by an unusual cell division after the egg has been fertilized by the sperm. […] Translocation Down syndrome. In a small number of people, Down syndrome can occur when a part of chromosome 21 becomes attached, also called translocated, onto another chromosome. This can happen before or at conception. The person has the usual two copies of chromosome 21, but also has extra genetic material from chromosome 21 attached to another chromosome.

• #5 Down Syndrome (Trisomy 21) – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/chromosome-and-gene-abnormalities/down-syndrome-trisomy-21

  Down syndrome is an abnormality of chromosome 21 that can cause intellectual disability, microcephaly, short stature, and characteristic facies. […] In approximately 95% of cases, Down syndrome is caused by nondisjunction resulting in an extra chromosome 21 (trisomy 21), which is typically maternally derived. […] Approximately 4% of Down syndrome cases are due to a translocation. […] Down syndrome is characterized by an extra chromosome 21. […] Down syndrome mosaicism presumably results from nondisjunction during cell division in the embryo. […] As with most conditions that result from chromosome imbalance, Down syndrome affects multiple systems and causes both structural and functional defects. […] Most affected people have some degree of cognitive impairment, ranging from severe to mild.

• #6 Genetics of Down syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Genetics_of_Down_syndrome

  Down syndrome is a chromosomal abnormality characterized by the presence of an extra copy of genetic material on chromosome 21, either in whole (trisomy 21) or part (such as due to translocations). […] Trisomy 21 (47,XY,+21) is caused by a meiotic nondisjunction event. […] Trisomy 21 is the cause of approximately 95% of observed Down syndrome, with 88% coming from nondisjunction in the maternal gamete and 8% coming from nondisjunction in the paternal gamete. […] The extra chromosome 21 material that causes Down syndrome may be due to a Robertsonian translocation. […] Translocation Down syndrome can be de novo; that is, not inherited but occurring at the time of an individual’s conception, or may be inherited from a parent with a balanced translocation. […] Mosaic Down syndrome is when some of the cells in the body do not have trisomy 21 and some cells have trisomy 21, an arrangement called a mosaic (46,XX/47,XX,+21). […] There is considerable variability in the fraction of cells with trisomy 21, both as a whole and tissue-by-tissue. […] Rarely, a region of chromosome 21 will undergo a duplication event.

• #7 Down syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Down_syndrome_pathophysiology

  Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome. […] Mechanisms leading to trisomy 21 include meiotic non-disjunction during meiosis I (majority) and meiosis II, Robertsonian translocation and mosaicism (rare). […] Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21. […] Disbilities found in Down syndrome patients are thought to arise secondary to varied genetic expression associated with the presence an extra 21st chromosome. […] Recent data points towards a number of susceptibility regions located on Hsa21, which are modified by other loci on Hsa21 and other genomic regions, increase the risk of developing specific DS associated phenotypes.

• #8 About Down Syndrome | National Down Syndrome Society (NDSS)

  https://ndss.org/about

  In translocation, which accounts for about 3% of cases of Down syndrome, the total number of chromosomes in the cells remains 46; however, an additional full or partial copy of chromosome 21 attaches to another chromosome, usually chromosome 14. […] There is no definitive scientific research that indicates that Down syndrome is caused by environmental factors or the parents activities before or during pregnancy.

• #9 Down syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Down_syndrome_pathophysiology

  Immaturity of the feto-placental unit has been proposed as an explanation for the reduced maternal serum alpha fetoprotein (AFP) and unconjugated oestriol (UE3) levels and increased hCG levels in Downs syndrome pregnancies. […] Approximately 4 percent cases of DS arise from Robertsonian translocation. […] This involves non-reciprocal chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21 and 22. […] Down syndrome resulting from mosaicism is very rare and accounts for around 1 percent of cases of DS. […] The phenotypical characrteristics produced in DS may be attributed to the disturbed gene expression due to trisomy 21. […] Patients with DS have learning and memory problems and exhibit differences in brain structure compared to the euploid population. […] Impaired synaptic plasticity in the interstriatal cholinergic system has been though to play a key role in DS-associated motor and cognitive defects. […] DS predisposes individuals to developing myeloproliferative dosorders, as well as acute megakaryocytic leukemia (AMKL) and acute lymphoblastic leukemia (ALL). […] Trisomy 21 lies at the heart of these abnormal cell proliferations.

• #10 International Mosaic Down Syndrome Association – Mosaic Down Syndrome

  https://www.imdsa.org/mosaic-down-syndrome

  Mosaic Down syndrome means that some cells of the body have trisomy 21, and some have the typical number of chromosomes. […] The initial zygote had three 21st chromosomes, which normally would result in simple trisomy 21, but during the course of cell division one or more cell lines lost one of the 21st chromosomes. […] The initial zygote had two 21st chromosomes, but during the course of cell division one of the 21st chromosomes were duplicated. […] At the present time, there is not much research on the similarities and differences between simple trisomy 21 and mosaic trisomy 21. […] The Department of Human Genetics at the Medical College of Virginia has had an ongoing study project of children with mosaic DS.

• #11 Mosaic Down syndrome: What you need to know

  https://www.massgeneral.org/children/down-syndrome/mosaic-down-syndrome

  Mosaic Down syndrome happens when an extra copy of chromosome 21 is present in some, but not all, of the bodys cells. […] An extra copy of chromosome 21 causes the differences we see in people with Down syndrome. […] Mosaic Down syndrome is caused by a random event shortly after the egg and sperm join together. […] When cells are dividing, some cells receive an extra copy of chromosome 21. Others do not. […] People with mosaic Down syndrome have some cells with two and some cells with three copies of chromosome 21. There is no way of knowing which, or how many, cells have two or three copies of chromosome 21.

• #12 Down syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Down_syndrome_pathophysiology

  In trisomy 21 the extra chromosome 21 is maternal in origin in about 95 percent of the cases, and paternal in only about 5 percent. […] In approximately 95% cases, the extra chromosome occurs as a result of meiotic nondisjunction (NDJ) or abnormal segregation of chromosomes. […] The process of oogenesis is lengthy and involves meiotic arrest, which makes predisposes the process to inappropriate segregation of chromosomes than spermatogenesis. […] In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle. […] Nondisjoined chromosomes often show recombination in various patterns and for trisomy 21, achiasmate meioses contribute about 45% of maternal meiotic error cases.

• #13 Down Syndrome | Birth Defects | CDC

  https://www.cdc.gov/birth-defects/about/down-syndrome.html

  Down syndrome is a condition in which a person has an extra copy of chromosome 21. Chromosomes are small „packages” of genes in the body’s cells, which determine how the body forms and functions. […] When babies are growing, the extra chromosome changes how their body and brain develop. This can cause both physical and mental challenges. […] We do not know for sure why Down syndrome occurs or how many different factors play a role. We do know that some things can affect your risk of having a baby with Down syndrome. […] One factor is your age when you get pregnant. The risk of having a baby with Down syndrome increases with age. This is especially the case if you are 35 years or older when you get pregnant. […] However, the majority of babies with Down syndrome are still born to mothers less than 35 years old. This is because there are many more births among younger women. […] Parents with one child with Down syndrome have a higher chance of having another child with Down syndrome regardless of age.

• #14 Down syndrome – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/down-syndrome/

  Down syndrome, also called trisomy 21, is the most common autosomal chromosomal irregularity, occurring in approximately 1:700 live births. Most individuals with Down syndrome have full trisomy 21, which occurs due to meiotic nondisjunction and results in a genotype with three complete copies of chromosome 21 and a total of 47 chromosomes. […] Pathogenesis: meiotic nondisjunction; Maternal nondisjunction occurs during meiosis I in approx. 70% of cases and during meiosis II in approx. 20% of cases. […] May occur due to paternal nondisjunction during spermatogenesis, more commonly during meiosis II (approx. 5% of cases). […] Translocation trisomy 21: Pathogenesis and karyotype: Carriers of balanced Robertsonian translocation have a normal phenotype. […] Mosaic trisomy 21: Pathogenesis: Nondisjunction during mitosis that occurs after fertilization. […] Down syndrome is the most common genetic cause of intellectual disability.

• #15 Down syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Down_syndrome_pathophysiology

  Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability. Additional copy of chromosome 21 results in elevated expression of many of the genes encoded on this chromosome, leading to variying expression of genes associated with this chromosome. […] Mechanisms leading to trisomy 21 include meiotic non-disjunction during meiosis I (majority) and meiosis II, Robertsonian translocation and mosaicism (rare). […] Absence of chiasmata and suboptimally placed chiasmata are the major mechanisms involved in non-disjunction of chromosome 21. […] Disbilities found in Down syndrome patients are thought to arise secondary to varied genetic expression associated with the presence an extra 21st chromosome. […] Recent data points towards a number of susceptibility regions located on Hsa21, which are modified by other loci on Hsa21 and other genomic regions, increase the risk of developing specific DS associated phenotypes.

• #16 What Causes Down Syndrome? | IntechOpen

  https://www.intechopen.com/chapters/75571

  Failure to nondisjunction in maternal meiosis I is associated with reduced recombination between unallocated chromosomes 21, suggesting an important role for pairing / recombination errors or reduced recombination in the etiology of trisomy 21. […] These findings are very effective in understanding the etiology of trisomy 21 and may explain why both maternal meiosis I and II errors are associated with increased maternal age. […] In the paternal nondisjunction of chromosome 21, there is mainly meiosis II error, as DNA polymorphisms show, in contrast to meiosis I errors and maternal nondisjunction. […] Two molecular studies with families with free trisomy 21 relapse showed that mosaicism in parents is an important etiological factor and that this possibility alone may explain recurrent trisomy 21 in most families.

• #17 Down syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Down_syndrome_pathophysiology

  In trisomy 21 the extra chromosome 21 is maternal in origin in about 95 percent of the cases, and paternal in only about 5 percent. […] In approximately 95% cases, the extra chromosome occurs as a result of meiotic nondisjunction (NDJ) or abnormal segregation of chromosomes. […] The process of oogenesis is lengthy and involves meiotic arrest, which makes predisposes the process to inappropriate segregation of chromosomes than spermatogenesis. […] In addition, increased maternal age leads to rapid degradation of cellular proteins involved in spindle formation, sister chromatid cohesion and anaphase separation of sister chromatids in oocytes during cell cycle. […] Nondisjoined chromosomes often show recombination in various patterns and for trisomy 21, achiasmate meioses contribute about 45% of maternal meiotic error cases.

• #18 Down Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK526016/

  Down syndrome (trisomy 21) is a genetic disorder caused by the presence of all or a portion of a third chromosome 21. […] It is the presence of all or part of the third copy of chromosome 21 that causes Down syndrome, the most common chromosomal abnormality occurring in humans. […] The majority of patients with Down syndrome have an extra copy of chromosome 21. There are different hypotheses related to the genetic basis of Down syndrome and the association of different genotypes with the phenotypes. Among them is gene dosage imbalance, in which there is an increased dosage or number of genes of Hsa21, which results in increased gene expansion. […] The critical region hypothesis is also well-known in this list. Down syndrome critical regions (DSCR) are a few chromosomal regions that are associated with partial trisomy for Has21. DSCR on 21q21.22 is responsible for many clinical features of Down syndrome.

• #19 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  The extra chromosome 21 affects almost every organ system and results in a wide spectrum of phenotypic consequences. These include life-threatening complications, clinically significant alteration of life course (eg, intellectual disability), and dysmorphic physical features. Down syndrome decreases prenatal viability and increases prenatal and postnatal morbidity. Affected children have delays in physical growth, maturation, bone development, and dental eruption. […] Two different hypotheses have been proposed to explain the mechanism of gene action in Down syndrome: developmental instability (ie, loss of chromosomal balance) and the so-called gene-dosage effect. According to the gene-dosage effect hypothesis, the genes located on chromosome 21 are overexpressed in cells and tissues of Down syndrome patients, and this contributes to the phenotypic abnormalities.

• #20 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  PGC-1 transcription and activity are positively regulated by Ca2+ signaling and negatively regulated by the Hsa21-coded corepressor NRIP1 (nuclear receptor interacting protein 1). […] Little is known about the mechanisms by which trisomy 21 causes the abnormal features typical of the DS phenotype, apart the knowledge that the dosage imbalance of genes on Hsa21 and the resulting dysregulation of genes mapping to different chromosomes share the responsibility for molecular dysfunctions in DS. […] Hsa21 gene expression was found globally upregulated 1.5-fold in trisomic samples, in full agreement with a gene-dosage effect. […] The dysregulation of one or more of these genes might account for mitochondrial alterations observed in DS. […] The knowledge of molecular bases of mitochondrial dysfunction is allowing to set-up most appropriate therapeutic solutions to counteract it.

• #21 Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3596542/

  The additional copy of Hsa21 results in elevated expression of many of the genes encoded on this chromosome, with varying expression levels in different tissues. The increased dosage of Hsa21 genes, and the dosage imbalance between Hsa21 and non-Hsa21 genes has been proposed to cause the plethora of phenotypic alterations that characterize DS. […] Current data suggest that a number of susceptibility regions located on Hsa21, which are modified by other loci on Hsa21 and elsewhere in the genome, increase the risk of developing specific DS associated phenotypes. […] Mouse models of DS are instrumental in identifying which genes contribute to DS phenotypes, and unraveling the mechanisms by which these phenotypes arise. […] The majority of mouse models used for DS research are either trisomic for large regions of Mmu16, 10, 17 or are transgenic animals used to investigate overexpression of a single gene.

• #22 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  The extra chromosome 21 affects almost every organ system and results in a wide spectrum of phenotypic consequences. These include life-threatening complications, clinically significant alteration of life course (eg, intellectual disability), and dysmorphic physical features. Down syndrome decreases prenatal viability and increases prenatal and postnatal morbidity. Affected children have delays in physical growth, maturation, bone development, and dental eruption. […] Two different hypotheses have been proposed to explain the mechanism of gene action in Down syndrome: developmental instability (ie, loss of chromosomal balance) and the so-called gene-dosage effect. According to the gene-dosage effect hypothesis, the genes located on chromosome 21 are overexpressed in cells and tissues of Down syndrome patients, and this contributes to the phenotypic abnormalities.

• #23 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  Containing about 33 genes, the Down syndrome critical region (DSCR), on chromosome 21 at 21q22.1-q22.3, plays a pivotal role in the pathophysiology of Down syndrome. Its significance was identified through studies of individuals with partial trisomies of chromosome 21, which linked the presence of extra copies of the DSCR to typical Down syndrome features. […] Within the DSCR, genes like DYRK1A and DSCR1/RCAN1 impact cognitive function and cardiac signaling, leading to intellectual disabilities and congenital heart defects. DYRK1A is also implicated in causing the characteristic facial dysmorphisms seen in Down syndrome, such as a flattened facial profile and slanted eyes. Outside the DSCR, genes like APP, influencing Alzheimer-like cognitive decline; CBS, affecting cardiovascular health; and SOD1, linked to oxidative stress and premature aging, further contribute to the Down syndrome phenotype.

• #24 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  Containing about 33 genes, the Down syndrome critical region (DSCR), on chromosome 21 at 21q22.1-q22.3, plays a pivotal role in the pathophysiology of Down syndrome. Its significance was identified through studies of individuals with partial trisomies of chromosome 21, which linked the presence of extra copies of the DSCR to typical Down syndrome features. […] Within the DSCR, genes like DYRK1A and DSCR1/RCAN1 impact cognitive function and cardiac signaling, leading to intellectual disabilities and congenital heart defects. DYRK1A is also implicated in causing the characteristic facial dysmorphisms seen in Down syndrome, such as a flattened facial profile and slanted eyes. Outside the DSCR, genes like APP, influencing Alzheimer-like cognitive decline; CBS, affecting cardiovascular health; and SOD1, linked to oxidative stress and premature aging, further contribute to the Down syndrome phenotype.

• #25 Down Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK526016/

  Down syndrome (trisomy 21) is a genetic disorder caused by the presence of all or a portion of a third chromosome 21. […] It is the presence of all or part of the third copy of chromosome 21 that causes Down syndrome, the most common chromosomal abnormality occurring in humans. […] The majority of patients with Down syndrome have an extra copy of chromosome 21. There are different hypotheses related to the genetic basis of Down syndrome and the association of different genotypes with the phenotypes. Among them is gene dosage imbalance, in which there is an increased dosage or number of genes of Hsa21, which results in increased gene expansion. […] The critical region hypothesis is also well-known in this list. Down syndrome critical regions (DSCR) are a few chromosomal regions that are associated with partial trisomy for Has21. DSCR on 21q21.22 is responsible for many clinical features of Down syndrome.

• #26 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  Containing about 33 genes, the Down syndrome critical region (DSCR), on chromosome 21 at 21q22.1-q22.3, plays a pivotal role in the pathophysiology of Down syndrome. Its significance was identified through studies of individuals with partial trisomies of chromosome 21, which linked the presence of extra copies of the DSCR to typical Down syndrome features. […] Within the DSCR, genes like DYRK1A and DSCR1/RCAN1 impact cognitive function and cardiac signaling, leading to intellectual disabilities and congenital heart defects. DYRK1A is also implicated in causing the characteristic facial dysmorphisms seen in Down syndrome, such as a flattened facial profile and slanted eyes. Outside the DSCR, genes like APP, influencing Alzheimer-like cognitive decline; CBS, affecting cardiovascular health; and SOD1, linked to oxidative stress and premature aging, further contribute to the Down syndrome phenotype.

• #27 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  Containing about 33 genes, the Down syndrome critical region (DSCR), on chromosome 21 at 21q22.1-q22.3, plays a pivotal role in the pathophysiology of Down syndrome. Its significance was identified through studies of individuals with partial trisomies of chromosome 21, which linked the presence of extra copies of the DSCR to typical Down syndrome features. […] Within the DSCR, genes like DYRK1A and DSCR1/RCAN1 impact cognitive function and cardiac signaling, leading to intellectual disabilities and congenital heart defects. DYRK1A is also implicated in causing the characteristic facial dysmorphisms seen in Down syndrome, such as a flattened facial profile and slanted eyes. Outside the DSCR, genes like APP, influencing Alzheimer-like cognitive decline; CBS, affecting cardiovascular health; and SOD1, linked to oxidative stress and premature aging, further contribute to the Down syndrome phenotype.

• #28

  https://omim.org/entry/190685

  Busciglio et al. (2002) found that astrocyte and neuronal cell cultures derived from Down syndrome fetal brains had increased intracellular levels of insoluble beta-amyloid-42 and decreased levels of secreted beta-amyloid. These abnormal patterns of APP (104760) processing were recapitulated in normal astrocytes by inhibition of mitochondrial metabolism. In addition, DS astrocytes showed impaired mitochondrial metabolism. Busciglio et al. (2002) postulated that mitochondrial dysfunction in Down syndrome may lead to intracellular deposition of beta-amyloid and increased neuronal vulnerability. […] Arron et al. (2006) reported that 2 genes, DSCR1 (RCAN1; 602917) and DYRK1A (600855), that lie within the critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors (see 600489), which are regulators of vertebrate development. Arron et al. (2006) used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors’ observations of calcineurin (see 114105)- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 are consistent with these predictions. Arron et al. (2006) suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. Arron et al. (2006) concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease.

• #29

  https://omim.org/entry/190685

  Busciglio et al. (2002) found that astrocyte and neuronal cell cultures derived from Down syndrome fetal brains had increased intracellular levels of insoluble beta-amyloid-42 and decreased levels of secreted beta-amyloid. These abnormal patterns of APP (104760) processing were recapitulated in normal astrocytes by inhibition of mitochondrial metabolism. In addition, DS astrocytes showed impaired mitochondrial metabolism. Busciglio et al. (2002) postulated that mitochondrial dysfunction in Down syndrome may lead to intracellular deposition of beta-amyloid and increased neuronal vulnerability. […] Arron et al. (2006) reported that 2 genes, DSCR1 (RCAN1; 602917) and DYRK1A (600855), that lie within the critical region of human chromosome 21 act synergistically to prevent nuclear occupancy of NFATc transcription factors (see 600489), which are regulators of vertebrate development. Arron et al. (2006) used mathematical modeling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. The authors’ observations of calcineurin (see 114105)- and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down syndrome, and human trisomy 21 are consistent with these predictions. Arron et al. (2006) suggested that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down syndrome. Arron et al. (2006) concluded that more generally, their observations suggest that the destabilization of regulatory circuits can underlie human disease.

• #30 Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3596542/

  Elevated rates of neuronal apoptosis related to oxidative stress have been reported in DS. […] Moreover, recent research provides evidence that oxidative stress is elevated in the Ts1Cje mouse, suggesting that one or more genes trisomic in this model, likely contribute to DS-associated oxidative stress. […] Recently, it was proposed that DYRK1A contributes to DS neural phenotypes, such as impaired dendritic growth, by disturbing neuron-restrictive silencer factor (REST/NRSF) levels. […] MicroRNAs encoded by Hsa21 may also influence development of the brain; specifically trisomy of miR-155 and miR-802 has been suggested to regulate the expression of the methyl-CpG-binding-protein gene (MECP2), which is known to be important in neurodevelopment. […] DS is complex disorder and dissecting the genetic and molecular processes underlying the syndrome requires many different complementary approaches, including the study of human data and mouse and other model organisms. […] However, several recent breakthroughs have increased our understanding of the effects of Hsa21 trisomy. Combining information from studies of people with DS with the power of mouse models of trisomy has enabled genetic associations to be tested and continues to lead to the identification of genes that cause DS-associated pathology. Significant advances in basic research have been instrumental in determining the molecular mechanisms underlying these phenotypes leading to useful therapeutic interventions.

• #31 Down syndrome is caused partly by gene under-expression, not just over-expression

  https://www.jax.org/news-and-insights/2010/april/down-syndrome-is-caused-partly-by-gene-under-expression-not-just-over-expre

  Down syndrome phenotypes are caused by over-expression of trisomy chr 21 genes. However, gene under-expression is also partly to blame. […] Elton and his team found that two micro RNAs (miRNAs), miR-155 and miR-802, encoded in trisomy chr 21 genes inhibit the expression of the transcription factor methyl-CpG-binding protein 2 (MeCP2), resulting in the upregulation of CREB1/Creb1 and downregulation of MEF2C/Mef2c, two genes that control neuronal plasticity and development. […] All the evidence indicated that downregulation of this gene might result in Down syndrome phenotypes. […] MeCP2’s absence contributes to cognitive problems associated with Down syndrome. […] Future research on the role of other chr 21 miRNAs in the pathogenesis of Down syndrome will undoubtedly uncover other key pathways and perhaps help scientists develop therapies that can attenuate, perhaps even reverse, some of Down syndrome’s effects.

• #32 Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction – World Mitochondria Society

  https://wms-site.com/alert-on-mitochondria/849-down-syndrome-role-of-hydrogen-sulfide-overproduction-in-the-pathogenesis-of-mitochondrial-dysfunction

  Prof. Szabo will give a talk entitled „Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction” during the congress which will be held on October 29-30, 2020 in Berlin, Germany. […] An increased expression of CBS and the consequent overproduction of H2S is well documented in individuals with Down syndrome (DS). […] Two decades ago, it has been proposed that a toxic overproduction of H2S importantly contributes to the metabolic and neurological deficits associated with DS. […] The present talk will present recent data generated in human dermal fibroblasts showing that DS cells overproduce H2S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. […] Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: this results in the improvement of mitochondrial function in DS cells.

• #33 Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction – World Mitochondria Society

  https://wms-site.com/alert-on-mitochondria/849-down-syndrome-role-of-hydrogen-sulfide-overproduction-in-the-pathogenesis-of-mitochondrial-dysfunction

  Prof. Szabo will give a talk entitled „Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction” during the congress which will be held on October 29-30, 2020 in Berlin, Germany. […] An increased expression of CBS and the consequent overproduction of H2S is well documented in individuals with Down syndrome (DS). […] Two decades ago, it has been proposed that a toxic overproduction of H2S importantly contributes to the metabolic and neurological deficits associated with DS. […] The present talk will present recent data generated in human dermal fibroblasts showing that DS cells overproduce H2S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. […] Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: this results in the improvement of mitochondrial function in DS cells.

• #34 Trisomy 21/Down Syndrome – EyeWiki

  https://eyewiki.org/Trisomy_21/Down_Syndrome

  Down syndrome is associated with impaired cortical development during pregnancy and early childhood, as well as accelerated brain atrophy as individuals age. It is hypothesized that abnormalities of the visual cortex may contribute to the decreased visual acuity often encountered in patients with Down syndrome, including those with relatively normal ocular anatomy.

• #35 Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3596542/

  In this review, we highlight recent developments in understanding how overexpression of Hsa21 genes leads to many of the features of DS. We focus on key areas including brain, heart and cancer, as these are currently the most developed in our understanding of the molecular pathogenesis of DS. […] The over-expression of a number of Hsa21 genes has been implicated in learning and memory deficits in single gene transgenic mouse models, suggesting that trisomy of these genes may contribute to learning disability in DS individuals. […] Recent evidence has emerged for a possible role in brain function of dopey family member 2 (DOPEY2) and Down syndrome cell adhesion molecule (DSCAM), two Hsa21 genes known to be involved in learning and memory. […] Neurodevelopment is known to be altered in people with DS. […] The common region that is trisomic between these two mouse models contains approximately 86 genes, suggesting that this trisomic segment contains the causal dosage-sensitive genes for these detrimental developmental phenotypes.

• #36

  https://link.springer.com/article/10.1007/s00415-023-11890-0

  Hence, studying the morphologic characteristics of diseased neurons on a cellular level can help achieve a better understanding of their pathology and give insights for further research into novel therapies. […] This paper aims to discuss and review the mechanisms of over-inhibition and the morphological abnormalities seen in PNs within the brains of DS patients and to provide a more holistic approach to understanding the plausible causes of such cognitive impairments. […] Neuronal dysfunction in DS begins as early as the embryonic stage, as fetal DS brains exhibit abnormal levels of neurotransmitters critical for normal brain development. […] The deficiency of GABA in the developing brain can lead to over-inhibition by loss of excitatory synaptic transmission. […] Over-inhibition was also believed to be attributed to the elevated concentrations of GABA at the synapses in the brains of DS patients.

• #37 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | Picower Institute

  https://picower.mit.edu/news/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-state

  Extra chromosome alters chromosomal conformation and DNA accessibility across the whole genome in neural progenitor cells, disrupting gene transcription and cell functions much like in cellular aging […] In Down syndrome, the third copy of chromosome 21 causes a reorganization of the 3D configuration of the entire genome in a key cell type of the developing brain, a new study shows. […] The resulting disruption of gene transcription and cell function are so similar to those seen in cellular aging, or senescence, that the scientists leading the study found they could use anti-senescence drugs to correct them in cell cultures. […] There is a cell-type specific genome-wide disruption that is independent of the gene dosage response, Meharena said. Its a very similar phenomenon to whats observed in senescence. This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome.

• #38 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | Picower Institute

  https://picower.mit.edu/news/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-state

  Overall, the picture that emerged in NPCs was that the presence of a third copy causes all the other chromosomes to squish inward, not unlike when people in a crowded elevator must narrow their stance when one more person squeezes in. […] These changes and differences in DNA conformation within the cell nucleus lead to changes in how genes are transcribed and therefore expressed, causing important differences in cell function that affect brain development. […] A new study’s findings indicate that amid trisomy 21, neural progenitor cells experience a genome-wide chromosomal reorganization leading to a senescence-like response including altered chromatin states and gene transcription. […] A question raised by the new findings, therefore, is whether the senescence-like character of Down syndrome NPCs is indeed the result of an aneuploidy induced stress and if so, exactly what that stress is.

• #39 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | Picower Institute

  https://picower.mit.edu/news/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-state

  Overall, the picture that emerged in NPCs was that the presence of a third copy causes all the other chromosomes to squish inward, not unlike when people in a crowded elevator must narrow their stance when one more person squeezes in. […] These changes and differences in DNA conformation within the cell nucleus lead to changes in how genes are transcribed and therefore expressed, causing important differences in cell function that affect brain development. […] A new study’s findings indicate that amid trisomy 21, neural progenitor cells experience a genome-wide chromosomal reorganization leading to a senescence-like response including altered chromatin states and gene transcription. […] A question raised by the new findings, therefore, is whether the senescence-like character of Down syndrome NPCs is indeed the result of an aneuploidy induced stress and if so, exactly what that stress is.

• #40

  https://link.springer.com/article/10.1007/s00415-023-11890-0

  Over-inhibition can also be attributed to the number of GABAergic neurons and the alterations in synaptic connections. […] Hence, overexpression may influence the normal function of inhibitory circuits and contribute to the cognitive deficits observed in DS patients. […] Studies also pointed to reduced glutamatergic activity in DS patients, offsetting the balance between Glutamatergic and GABAergic activity. Such findings were attributed to a deficiency in the SNX27 gene. […] The extra copy of chromosome 21 has also contributed to abnormalities in brain structure and neuronal functioning, contributing to varying levels of intellectual disabilities.

• #41

  https://link.springer.com/article/10.1007/s00415-023-11890-0

  Over-inhibition can also be attributed to the number of GABAergic neurons and the alterations in synaptic connections. […] Hence, overexpression may influence the normal function of inhibitory circuits and contribute to the cognitive deficits observed in DS patients. […] Studies also pointed to reduced glutamatergic activity in DS patients, offsetting the balance between Glutamatergic and GABAergic activity. Such findings were attributed to a deficiency in the SNX27 gene. […] The extra copy of chromosome 21 has also contributed to abnormalities in brain structure and neuronal functioning, contributing to varying levels of intellectual disabilities.

• #42

  https://link.springer.com/article/10.1007/s00415-023-11890-0

  Over-inhibition can also be attributed to the number of GABAergic neurons and the alterations in synaptic connections. […] Hence, overexpression may influence the normal function of inhibitory circuits and contribute to the cognitive deficits observed in DS patients. […] Studies also pointed to reduced glutamatergic activity in DS patients, offsetting the balance between Glutamatergic and GABAergic activity. Such findings were attributed to a deficiency in the SNX27 gene. […] The extra copy of chromosome 21 has also contributed to abnormalities in brain structure and neuronal functioning, contributing to varying levels of intellectual disabilities.

• #43

  https://link.springer.com/article/10.1007/s00415-023-11890-0

  The most common genetic cause of intellectual disability is Down syndrome (DS), trisomy 21. It commonly results from three copies of human chromosome 21 (HC21). There are no mutations or deletions involved in DS. Instead, the phenotype is caused by altered transcription of the genes on HC21. These transcriptional variations are responsible for a myriad of symptoms affecting every organ system. […] In this literature review, we discuss the mechanisms of neuronal over-inhibition, abnormal morphology, and other genetic factors in contributing to the development of ID in DS patients and to gain a holistic understanding of ID in DS patients. […] One mechanism of interest is the morphological changes of neurons in DS patients. […] However, little research has been devoted to understanding the association between the neuronal morphological discrepancies seen in DS brains and ID.

• #44

  https://link.springer.com/article/10.1007/s00415-023-11890-0

  Hence, studying the morphologic characteristics of diseased neurons on a cellular level can help achieve a better understanding of their pathology and give insights for further research into novel therapies. […] This paper aims to discuss and review the mechanisms of over-inhibition and the morphological abnormalities seen in PNs within the brains of DS patients and to provide a more holistic approach to understanding the plausible causes of such cognitive impairments. […] Neuronal dysfunction in DS begins as early as the embryonic stage, as fetal DS brains exhibit abnormal levels of neurotransmitters critical for normal brain development. […] The deficiency of GABA in the developing brain can lead to over-inhibition by loss of excitatory synaptic transmission. […] Over-inhibition was also believed to be attributed to the elevated concentrations of GABA at the synapses in the brains of DS patients.

• #45 Down Syndrome (Trisomy 21) – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/chromosome-and-gene-abnormalities/down-syndrome-trisomy-21

  Approximately 50% of affected neonates have congenital heart disease; ventricular septal defect and atrioventricular canal defect are most common. […] Many people develop endocrinopathies, including thyroid disease (most often hypothyroidism) and diabetes. […] The aging process seems to be accelerated. […] The underlying genetic abnormality cannot be cured. […] Some congenital cardiac or gastrointestinal anomalies are repaired surgically. […] Down syndrome involves an extra chromosome 21, either a separate chromosome or a translocation onto another chromosome. […] Life expectancy is decreased primarily because of heart disease and, to a lesser degree, increased susceptibility to infections, acute myelocytic leukemia, and early-onset Alzheimer disease.

• #46 Scientists Discover Mechanism Affecting Heart Development in Down Syndrome | Global Down Syndrome Foundation

  https://www.globaldownsyndrome.org/scientists-discover-mechanism-affecting-heart-development-in-down-syndrome/

  During their investigation, they made a noteworthy observation: trisomy 21 hindered the process of cardiogenesis, and this malfunction appeared to be linked to an overactive cellular response to viral infections, specifically the interferon response. […] This finding suggests a potential therapeutic avenue for improving heart development in individuals with Down syndrome. […] Dr. Song expressed his surprise at the robust activation of the interferon response during the differentiation of pluripotent stem cells into heart muscle cells with trisomy 21. […] This discovery highlights the potential harmful effects of an abnormal interferon response on the proper formation of the heart in individuals with Down syndrome. […] Through their investigation, they made an additional breakthrough by uncovering that the interferon response actually impedes several crucial molecular processes necessary for proper heart development, including the Wnt signaling pathway.

• #47 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230621/Scientists-uncover-molecular-mechanism-contributing-to-defective-heart-development-in-Down-syndrome.aspx

  Infants born with Down syndrome, the genetic condition caused by an extra copy of chromosome 21, or trisomy 21, are highly predisposed to congenital heart defects. […] A recent study by scientists at the University of Colorado Anschutz Medical Campus reports the discovery of a molecular mechanism contributing to defective heart development in Down syndrome. […] They observed that trisomy 21 impaired cardiogenesis, and this malfunction was associated with hyperactivity in the cellular response to viral infections, known as the interferon response. […] The researchers continued their investigation into how exactly interferon hyperactivity impaired cardiogenesis, which led them to discover that the interferon response inhibits a series of key molecular events required for heart development, such as the Wnt signaling pathway.

• #48 Scientists Discover Mechanism Affecting Heart Development in Down Syndrome | Global Down Syndrome Foundation

  https://www.globaldownsyndrome.org/scientists-discover-mechanism-affecting-heart-development-in-down-syndrome/

  During their investigation, they made a noteworthy observation: trisomy 21 hindered the process of cardiogenesis, and this malfunction appeared to be linked to an overactive cellular response to viral infections, specifically the interferon response. […] This finding suggests a potential therapeutic avenue for improving heart development in individuals with Down syndrome. […] Dr. Song expressed his surprise at the robust activation of the interferon response during the differentiation of pluripotent stem cells into heart muscle cells with trisomy 21. […] This discovery highlights the potential harmful effects of an abnormal interferon response on the proper formation of the heart in individuals with Down syndrome. […] Through their investigation, they made an additional breakthrough by uncovering that the interferon response actually impedes several crucial molecular processes necessary for proper heart development, including the Wnt signaling pathway.

• #49 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230621/Scientists-uncover-molecular-mechanism-contributing-to-defective-heart-development-in-Down-syndrome.aspx

  According to Dr. Congwu Li, lead author of the paper, Too much interferon activity leads to too little Wnt signaling, which in turn impairs heart muscle cell function. […] These findings expand on a growing body of evidence demonstrating the harmful effects of interferon hyperactivity in Down syndrome, even during early stages of embryonic development.

• #50 Scientists Discover Mechanism Affecting Heart Development in Down Syndrome | Global Down Syndrome Foundation

  https://www.globaldownsyndrome.org/scientists-discover-mechanism-affecting-heart-development-in-down-syndrome/

  Unveiling this sequence of occurrences sheds light on possible approaches to mitigate abnormal heart development in Down syndrome by reducing interferon signaling and/or enhancing Wnt signaling. […] These findings hold great significance as they propose a prospective pharmacological approach for prenatal intervention in mitigating one of the severe consequences of trisomy 21. […] These findings contribute to the expanding body of evidence highlighting the detrimental consequences of excessive interferon activity in Down syndrome, even in the initial phases of embryonic development. […] The outcomes further endorse the notion that several distinctive features of Down syndrome stem from persistent immune system dysregulation throughout life, and that reinstating immune equilibrium could yield therapeutic advantages.

• #51 Gene behind Down syndrome heart defects identified | UCL News – UCL – University College London

  https://www.ucl.ac.uk/news/2024/jan/gene-behind-down-syndrome-heart-defects-identified

  A gene that causes heart defects in Down syndrome has been identified by researchers at UCL and the Francis Crick Institute. […] The team found that reducing the overactivity of this gene partially reversed these defects in mice, paving the way for potential future therapies for heart conditions in people with Down syndrome. […] Consequently, better treatment options are needed, and this must be guided by knowledge of which of the extra 230 genes on chromosome 21 are responsible for the heart defects. […] Using genetic mapping, the researchers identified a gene on human chromosome 21 called Dyrk1a, which causes heart defects when three copies of the gene are present in the mouse model of Down syndrome. […] An extra copy of Dyrk1a turned down the activity of genes required for cell division in the developing heart and the function of the mitochondria, which produce energy for the cells. These changes correlated with a failure to correctly separate the chambers of the heart.

• #52 Gene behind Down syndrome heart defects identified | UCL News – UCL – University College London

  https://www.ucl.ac.uk/news/2024/jan/gene-behind-down-syndrome-heart-defects-identified

  A gene that causes heart defects in Down syndrome has been identified by researchers at UCL and the Francis Crick Institute. […] The team found that reducing the overactivity of this gene partially reversed these defects in mice, paving the way for potential future therapies for heart conditions in people with Down syndrome. […] Consequently, better treatment options are needed, and this must be guided by knowledge of which of the extra 230 genes on chromosome 21 are responsible for the heart defects. […] Using genetic mapping, the researchers identified a gene on human chromosome 21 called Dyrk1a, which causes heart defects when three copies of the gene are present in the mouse model of Down syndrome. […] An extra copy of Dyrk1a turned down the activity of genes required for cell division in the developing heart and the function of the mitochondria, which produce energy for the cells. These changes correlated with a failure to correctly separate the chambers of the heart.

• #53 Gene behind Down syndrome heart defects identified | UCL News – UCL – University College London

  https://www.ucl.ac.uk/news/2024/jan/gene-behind-down-syndrome-heart-defects-identified

  The team found that while three copies of Dyrk1a is required to cause heart defects in mice, another unknown gene is also involved. The team is currently searching for this second gene. […] Our research shows that inhibiting DYRK1A can partially reverse changes in mouse hearts, suggesting that this may be a useful therapeutic approach. […] The hope is that a DYRK1A inhibitor could have an effect on the heart later in pregnancy, or even better after birth. These are possibilities we are currently investigating. […] It was remarkable that just restoring the copy number of one gene from three to two reversed the heart defects in the mouse model for Down syndrome. Were now aiming to understand which of the other genes on this extra chromosome are involved. Even though Dyrk1a isnt the only gene involved, its clearly a major player in many different aspects of Down syndrome.

• #54 Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation

  https://www.mdpi.com/1422-0067/24/3/2918

  Down syndrome (DS), a complex disorder that is caused by the trisomy of chromosome 21 (Hsa21), is a major cause of congenital heart defects (CHD). […] The overexpression of Hsa21 genes likely underlies the molecular mechanisms that contribute to CHD, even though the genes responsible for CHD could only be located in a critical region of Hsa21. […] A role in causing CHD has been attributed not only to protein-coding Hsa21 genes, but also to genes on other chromosomes, as well as miRNAs and lncRNAs. […] It is likely that the contribution of more than one gene is required, and that the overexpression of Hsa21 genes acts in combination with other genetic events, such as specific mutations or polymorphisms, amplifying their effect. […] Moreover, a key function in determining alterations in cardiac morphogenesis might be played by ECM.

• #55 Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation

  https://www.mdpi.com/1422-0067/24/3/2918

  A large number of genes encoding ECM proteins are overexpressed in trisomic human fetal hearts, and many of them appear to be under the control of a Hsa21 gene, the RUNX1 transcription factor. […] In this review, we address the role of genes mapping to Hsa21 and other chromosomes in the development of the heart and in molecular mechanisms responsible for CHD. […] The transcriptional profile of human hearts from DS fetuses demonstrated that most Hsa21 genes are overexpressed in the developing heart due to gene dosage. […] The notion that only half of DS subjects present CHD suggests that some other events, such as copy number variations (CNV), SNPs, or other genetic anomalies, may concur with trisomy to alter heart development. […] The dysregulation and pathogenic mutations or polymorphisms of genes involved in cardiogenesis may concur to generate CHD.

• #56 Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation

  https://www.mdpi.com/1422-0067/24/3/2918

  For this reason, the dysregulated expression and/or organization of ECM components in DS may be responsible for altered heart morphogenesis. […] It has been proposed and demonstrated that the upregulation of RUNX1, a gene mapping to Hsa21, contributes to the overexpression of ECM-related genes in trisomic cells and also accounts for the decreased migration of trisomic fibroblasts.

• #57 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  Abnormal physiologic functioning affects thyroid metabolism and intestinal malabsorption. Patients with trisomy 21 have an increased risk of obesity. Frequent infections are presumably due to impaired immune responses, and the incidence of autoimmunity, including as seen in the development of hypothyroidism and rare Hashimoto thyroiditis, is increased. […] Patients with Down syndrome have decreased buffering of physiologic reactions, resulting in hypersensitivity to pilocarpine and abnormal responses on sensory-evoked electroencephalographic (EEG) tracings. Children with leukemic Down syndrome also have hyperreactivity to methotrexate. […] Decreased buffering of metabolic processes results in a predisposition to hyperuricemia and increased insulin resistance. Diabetes mellitus develops in many affected patients. Premature senescence causes cataracts and Alzheimer disease.

• #58 Trisomy 21 – Embryology

  https://embryology.med.unsw.edu.au/embryology/index.php?title=Trisomy_21

  Down syndrome or trisomy 21 is caused by nondisjunction of chromosome 21 in a parent who is chromosomally normal and is one of the most common chromosomal aneuploidy abnormalities in liveborn children. […] Despite the fact that more than 50 years have passed since the discovery of its genetic aberrations, the exact pathogenesis of the DS phenotype has remained largely unexplained. It was recently hypothesized that the DS pathogenesis involves complex (epi)genetic, molecular and cellular determinants. […] Trisomy of chromosome 21, the genetic cause of Down syndrome, has the potential to alter expression of genes on chromosome 21, as well as other locations throughout the genome. These transcriptome changes are likely to underlie the Down syndrome clinical phenotypes. […] Although it is clear that trisomy 21 causes Down syndrome, the molecular events acting downstream of the trisomy remain ill defined. Using complementary genomics analyses, we identified the interferon pathway as the major signaling cascade consistently activated by trisomy 21 in human cells.

• #59 Scientists Discover Mechanism Affecting Heart Development in Down Syndrome | Global Down Syndrome Foundation

  https://www.globaldownsyndrome.org/scientists-discover-mechanism-affecting-heart-development-in-down-syndrome/

  Unveiling this sequence of occurrences sheds light on possible approaches to mitigate abnormal heart development in Down syndrome by reducing interferon signaling and/or enhancing Wnt signaling. […] These findings hold great significance as they propose a prospective pharmacological approach for prenatal intervention in mitigating one of the severe consequences of trisomy 21. […] These findings contribute to the expanding body of evidence highlighting the detrimental consequences of excessive interferon activity in Down syndrome, even in the initial phases of embryonic development. […] The outcomes further endorse the notion that several distinctive features of Down syndrome stem from persistent immune system dysregulation throughout life, and that reinstating immune equilibrium could yield therapeutic advantages.

• #60 Uncovering the mechanisms behind autoimmunity in Down’s syndrome

  https://frontlinegenomics.com/uncovering-the-mechanisms-behind-autoimmunity-in-downs-syndrome/

  A study, recently published in Nature, has revealed the mechanisms underpinning autoimmune susceptibility in individuals with Down’s syndrome. The researchers identified chronic expression of certain immune cells, particularly those that can be described as “autoimmune-prone.” […] The condition is characterised by various symptoms including learning difficulties. However, a lesser known (yet often severe) aspect of Down’s syndrome is an increased susceptibility to infectious diseases and autoimmune conditions. […] In their analysis, they identified rogue immune cells that may explain the phenomenon of increased autoimmune susceptibility. […] The researchers then measured the levels in samples from patients with respiratory viruses, revealing that in many individuals with Down’s syndrome, basal levels were often similar or higher than in patients suffering from COVID-19. This implies some level of constant immune response, regardless of the presence of any disease.

• #61 Uncovering the mechanisms behind autoimmunity in Down’s syndrome

  https://frontlinegenomics.com/uncovering-the-mechanisms-behind-autoimmunity-in-downs-syndrome/

  A study, recently published in Nature, has revealed the mechanisms underpinning autoimmune susceptibility in individuals with Down’s syndrome. The researchers identified chronic expression of certain immune cells, particularly those that can be described as “autoimmune-prone.” […] The condition is characterised by various symptoms including learning difficulties. However, a lesser known (yet often severe) aspect of Down’s syndrome is an increased susceptibility to infectious diseases and autoimmune conditions. […] In their analysis, they identified rogue immune cells that may explain the phenomenon of increased autoimmune susceptibility. […] The researchers then measured the levels in samples from patients with respiratory viruses, revealing that in many individuals with Down’s syndrome, basal levels were often similar or higher than in patients suffering from COVID-19. This implies some level of constant immune response, regardless of the presence of any disease.

• #62 Uncovering the mechanisms behind autoimmunity in Down’s syndrome

  https://frontlinegenomics.com/uncovering-the-mechanisms-behind-autoimmunity-in-downs-syndrome/

  Consequently, the team chose to further investigate the presence of CD11c+ cells in individuals with Down’s syndrome. […] However, as there is an increased proportion of CD11c+ cells in individuals with Down’s syndrome, this would imply a heightened level of CD11c+-derived autoimmunity. […] These two features led the researchers to the conclusion that cytokine and T-cell mediated activation of CD11c+ cells was likely a major driver of increased inflammatory responses and autoimmunity in those with Down’s syndrome. […] With an understanding of the underlying cause, there is now potential for autoimmune conditions in those with Down’s syndrome to be addressed at the source, rather than simply treating the symptoms. […] Lead author Dusan Bugnovich stated: “Available drugs such as tocilizumab and a variety of JAK inhibitors could potentially tame this inflammation.”

• #63 Uncovering the mechanisms behind autoimmunity in Down’s syndrome

  https://frontlinegenomics.com/uncovering-the-mechanisms-behind-autoimmunity-in-downs-syndrome/

  Consequently, the team chose to further investigate the presence of CD11c+ cells in individuals with Down’s syndrome. […] However, as there is an increased proportion of CD11c+ cells in individuals with Down’s syndrome, this would imply a heightened level of CD11c+-derived autoimmunity. […] These two features led the researchers to the conclusion that cytokine and T-cell mediated activation of CD11c+ cells was likely a major driver of increased inflammatory responses and autoimmunity in those with Down’s syndrome. […] With an understanding of the underlying cause, there is now potential for autoimmune conditions in those with Down’s syndrome to be addressed at the source, rather than simply treating the symptoms. […] Lead author Dusan Bugnovich stated: “Available drugs such as tocilizumab and a variety of JAK inhibitors could potentially tame this inflammation.”

• #64 Uncovering the mechanisms behind autoimmunity in Down’s syndrome

  https://frontlinegenomics.com/uncovering-the-mechanisms-behind-autoimmunity-in-downs-syndrome/

  Consequently, the team chose to further investigate the presence of CD11c+ cells in individuals with Down’s syndrome. […] However, as there is an increased proportion of CD11c+ cells in individuals with Down’s syndrome, this would imply a heightened level of CD11c+-derived autoimmunity. […] These two features led the researchers to the conclusion that cytokine and T-cell mediated activation of CD11c+ cells was likely a major driver of increased inflammatory responses and autoimmunity in those with Down’s syndrome. […] With an understanding of the underlying cause, there is now potential for autoimmune conditions in those with Down’s syndrome to be addressed at the source, rather than simply treating the symptoms. […] Lead author Dusan Bugnovich stated: “Available drugs such as tocilizumab and a variety of JAK inhibitors could potentially tame this inflammation.”

• #65 Down syndrome and leukemia: insights into leukemogenesis and translational targets – Mateos – Translational Pediatrics

  https://tp.amegroups.org/article/view/6268/html

  Children with Down syndrome (DS) have a significantly increased risk of childhood leukemia, in particular acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (DS-ALL). […] This model represents an important multi-step process of leukemogenesis, and further study is required to identify therapeutic targets to potentially prevent development of leukemia. […] ML-DS is characterised by transforming events that occur in the fetal and newborn period. […] The first hit is the presence of trisomy 21, which leads to increased proliferation of megakaryocyte progenitors (MKPs) in the fetal liver. The subsequent transforming event is a mutation in GATA binding protein 1 (GATA1) which gives rise to TMD. […] The acquisition of trisomy 21 alone is the first hit, as trisomy 21 without GATA1 mutation leads to altered myeloid progenitor self-renewal, altered lineage development and increased clonogenicity of MKPs in human fetal livers.

• #66 Down syndrome and leukemia: insights into leukemogenesis and translational targets – Mateos – Translational Pediatrics

  https://tp.amegroups.org/article/view/6268/html

  Children with Down syndrome (DS) have a significantly increased risk of childhood leukemia, in particular acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (DS-ALL). […] This model represents an important multi-step process of leukemogenesis, and further study is required to identify therapeutic targets to potentially prevent development of leukemia. […] ML-DS is characterised by transforming events that occur in the fetal and newborn period. […] The first hit is the presence of trisomy 21, which leads to increased proliferation of megakaryocyte progenitors (MKPs) in the fetal liver. The subsequent transforming event is a mutation in GATA binding protein 1 (GATA1) which gives rise to TMD. […] The acquisition of trisomy 21 alone is the first hit, as trisomy 21 without GATA1 mutation leads to altered myeloid progenitor self-renewal, altered lineage development and increased clonogenicity of MKPs in human fetal livers.

• #67 Down syndrome and leukemia: insights into leukemogenesis and translational targets – Mateos – Translational Pediatrics

  https://tp.amegroups.org/article/view/6268/html

  Children with Down syndrome (DS) have a significantly increased risk of childhood leukemia, in particular acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (DS-ALL). […] This model represents an important multi-step process of leukemogenesis, and further study is required to identify therapeutic targets to potentially prevent development of leukemia. […] ML-DS is characterised by transforming events that occur in the fetal and newborn period. […] The first hit is the presence of trisomy 21, which leads to increased proliferation of megakaryocyte progenitors (MKPs) in the fetal liver. The subsequent transforming event is a mutation in GATA binding protein 1 (GATA1) which gives rise to TMD. […] The acquisition of trisomy 21 alone is the first hit, as trisomy 21 without GATA1 mutation leads to altered myeloid progenitor self-renewal, altered lineage development and increased clonogenicity of MKPs in human fetal livers.

• #68 Down syndrome and leukemia: insights into leukemogenesis and translational targets – Mateos – Translational Pediatrics

  https://tp.amegroups.org/article/view/6268/html

  Somatic GATA1 mutation is identified as the second hit, and it is thought to block MK differentiation. […] GATA1 gene mutation leads to sole production of a truncated GATA1 protein, called GATA1s. […] The presence of GATA1s is thought to impair GATA1-mediated regulation of other transcription factors, including GATA2, MYB, MYC and IKAROS family zinc finger 1 (IKZF1) in fetal MKs. […] It is highly likely that additional transforming events, or hits, are involved in this leukemogenic process. […] Current knowledge regarding the ability to detect and quantify GATA1s or GATA1 mutations from a clinical TMD episode through to either TMD resolution or evolution to ML-DS is limited. […] Therefore, the ultimate aim is to identify novel therapeutic targets that may improve outcome for all children with DS, pre-leukemia and leukemia.

• #69 Down syndrome and leukemia: insights into leukemogenesis and translational targets – Mateos – Translational Pediatrics

  https://tp.amegroups.org/article/view/6268/html

  Somatic GATA1 mutation is identified as the second hit, and it is thought to block MK differentiation. […] GATA1 gene mutation leads to sole production of a truncated GATA1 protein, called GATA1s. […] The presence of GATA1s is thought to impair GATA1-mediated regulation of other transcription factors, including GATA2, MYB, MYC and IKAROS family zinc finger 1 (IKZF1) in fetal MKs. […] It is highly likely that additional transforming events, or hits, are involved in this leukemogenic process. […] Current knowledge regarding the ability to detect and quantify GATA1s or GATA1 mutations from a clinical TMD episode through to either TMD resolution or evolution to ML-DS is limited. […] Therefore, the ultimate aim is to identify novel therapeutic targets that may improve outcome for all children with DS, pre-leukemia and leukemia.

• #70

  https://haematologica.org/article/view/haematol.2023.283225

  Mechanistically, RUNX1A binds to the MYC binding partner MAX allowing for upregulation of a MYC/E2F-induced proliferative program. […] Interestingly, GATA1s plus RUNX1A synergize with miR-125b expression to further enhance a malignant phenotype. […] The most frequently mutated protein complex in ML-DS is cohesin, one of the main drivers of three-dimensional genome folding. […] Cohesin and CTCF are responsible for partitioning the genome into topologically associating domains, which are functional units of gene regulation that both facilitate and limit the range of action of enhancer-promoter interactions. […] The inability to respond to inflammatory signals was linked to the incapacity of AML cells to differentiate, as normal HSPC differentiate in response to inflammation. […] Overall, challenges of ML-DS treatment include how to perform risk stratification integrating new information about molecular subgroups of ML-DS, how to reduce relapse events, how to improve outcomes for refractory and relapsed ML-DS and how to get access to new agents for patients with DS, who historically were routinely excluded from early phase trials.

• #71

  https://haematologica.org/article/view/haematol.2023.283225

  Mechanistically, RUNX1A binds to the MYC binding partner MAX allowing for upregulation of a MYC/E2F-induced proliferative program. […] Interestingly, GATA1s plus RUNX1A synergize with miR-125b expression to further enhance a malignant phenotype. […] The most frequently mutated protein complex in ML-DS is cohesin, one of the main drivers of three-dimensional genome folding. […] Cohesin and CTCF are responsible for partitioning the genome into topologically associating domains, which are functional units of gene regulation that both facilitate and limit the range of action of enhancer-promoter interactions. […] The inability to respond to inflammatory signals was linked to the incapacity of AML cells to differentiate, as normal HSPC differentiate in response to inflammation. […] Overall, challenges of ML-DS treatment include how to perform risk stratification integrating new information about molecular subgroups of ML-DS, how to reduce relapse events, how to improve outcomes for refractory and relapsed ML-DS and how to get access to new agents for patients with DS, who historically were routinely excluded from early phase trials.

• #72

  https://haematologica.org/article/view/haematol.2023.283225

  Children with Down syndrome (DS, trisomy 21) are at a significantly higher risk of developing acute leukemia compared to the overall population. […] Understanding the mechanisms of leukemia predisposition related to constitutive trisomy 21 (T21) and characterizing the genetic landscape and multistep pathogenesis of DS-associated leukemias have led to major discoveries over the last two decades. […] The role of T21 in disrupting fetal hematopoiesis occurs through genome-wide transcriptional perturbation, including genes encoding transcription factors, pro-inflammatory cytokines, and various microRNA in fetal hematopoietic stem and progenitor cells and in stromal cells. […] The transcription factor GATA1 is a master regulator of blood cell development, especially erythropoiesis and megakaryopoiesis, and mutations are found in virtually all TAM and ML-DS cases.

• #73

  https://haematologica.org/article/view/haematol.2023.283225

  Children with Down syndrome (DS, trisomy 21) are at a significantly higher risk of developing acute leukemia compared to the overall population. […] Understanding the mechanisms of leukemia predisposition related to constitutive trisomy 21 (T21) and characterizing the genetic landscape and multistep pathogenesis of DS-associated leukemias have led to major discoveries over the last two decades. […] The role of T21 in disrupting fetal hematopoiesis occurs through genome-wide transcriptional perturbation, including genes encoding transcription factors, pro-inflammatory cytokines, and various microRNA in fetal hematopoietic stem and progenitor cells and in stromal cells. […] The transcription factor GATA1 is a master regulator of blood cell development, especially erythropoiesis and megakaryopoiesis, and mutations are found in virtually all TAM and ML-DS cases.

• #74

  https://haematologica.org/article/view/haematol.2023.283225

  Mechanistically, RUNX1A binds to the MYC binding partner MAX allowing for upregulation of a MYC/E2F-induced proliferative program. […] Interestingly, GATA1s plus RUNX1A synergize with miR-125b expression to further enhance a malignant phenotype. […] The most frequently mutated protein complex in ML-DS is cohesin, one of the main drivers of three-dimensional genome folding. […] Cohesin and CTCF are responsible for partitioning the genome into topologically associating domains, which are functional units of gene regulation that both facilitate and limit the range of action of enhancer-promoter interactions. […] The inability to respond to inflammatory signals was linked to the incapacity of AML cells to differentiate, as normal HSPC differentiate in response to inflammation. […] Overall, challenges of ML-DS treatment include how to perform risk stratification integrating new information about molecular subgroups of ML-DS, how to reduce relapse events, how to improve outcomes for refractory and relapsed ML-DS and how to get access to new agents for patients with DS, who historically were routinely excluded from early phase trials.

• #75 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  Down syndrome (DS) consists of a complex phenotype with constant features, such as mental retardation and hypotonia, and variable features, including heart defects and susceptibility to Alzheimers disease, type 2 diabetes, obesity and immune disorders. Overexpression of genes mapping to chromosome 21 (Hsa21) is directly or indirectly responsible for pathogenesis of DS phenotypic features, as overexpressed Hsa21 genes dysregulate several other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function. Recent studies highlight a link between mitochondrial dysfunction, consistently observed in DS subjects, and DS phenotype. […] Overexpression of genes mapping to chromosome 21 (Hsa21) is clearly responsible for pathogenesis of DS phenotypic features either in a direct or indirect manner, as overexpressed Hsa21 genes affect the regulation of several other genes mapping to different chromosomes. Many of these genes are involved in oxidative phosphorylation (OXPHOS) and more generally in the mitochondrial function.

• #76 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  Down syndrome (DS) consists of a complex phenotype with constant features, such as mental retardation and hypotonia, and variable features, including heart defects and susceptibility to Alzheimers disease, type 2 diabetes, obesity and immune disorders. Overexpression of genes mapping to chromosome 21 (Hsa21) is directly or indirectly responsible for pathogenesis of DS phenotypic features, as overexpressed Hsa21 genes dysregulate several other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function. Recent studies highlight a link between mitochondrial dysfunction, consistently observed in DS subjects, and DS phenotype. […] Overexpression of genes mapping to chromosome 21 (Hsa21) is clearly responsible for pathogenesis of DS phenotypic features either in a direct or indirect manner, as overexpressed Hsa21 genes affect the regulation of several other genes mapping to different chromosomes. Many of these genes are involved in oxidative phosphorylation (OXPHOS) and more generally in the mitochondrial function.

• #77 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  As fully described in the following paragraphs, the mitochondrial dysfunction together with the disruption of the mitochondrial network might concur to determine DS phenotypic traits. This suggests that correcting the mitochondrial defect might affect the severity of DS phenotype. […] The latest theories are reported about: (i) how mitochondrial malfunction may contribute to the pathogenesis of clinical manifestations of DS and (ii) how specific Hsa21 genes may be involved in determining the pathogenesis of mitochondrial dysfunction in DS. […] A common denominator of most of the events that affect mitochondrial function is the transcriptional coactivator PGC-1/PPARGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1alpha), a master regulator of mitochondrial activity. PGC-1, through the interaction with transcriptional partners, such as NRF1, ERRa, PPARs and YY1, promotes mitochondrial biogenesis and regulates mitochondrial respiratory capacity.

• #78 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  As fully described in the following paragraphs, the mitochondrial dysfunction together with the disruption of the mitochondrial network might concur to determine DS phenotypic traits. This suggests that correcting the mitochondrial defect might affect the severity of DS phenotype. […] The latest theories are reported about: (i) how mitochondrial malfunction may contribute to the pathogenesis of clinical manifestations of DS and (ii) how specific Hsa21 genes may be involved in determining the pathogenesis of mitochondrial dysfunction in DS. […] A common denominator of most of the events that affect mitochondrial function is the transcriptional coactivator PGC-1/PPARGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1alpha), a master regulator of mitochondrial activity. PGC-1, through the interaction with transcriptional partners, such as NRF1, ERRa, PPARs and YY1, promotes mitochondrial biogenesis and regulates mitochondrial respiratory capacity.

• #79 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  PGC-1 transcription and activity are positively regulated by Ca2+ signaling and negatively regulated by the Hsa21-coded corepressor NRIP1 (nuclear receptor interacting protein 1). […] Little is known about the mechanisms by which trisomy 21 causes the abnormal features typical of the DS phenotype, apart the knowledge that the dosage imbalance of genes on Hsa21 and the resulting dysregulation of genes mapping to different chromosomes share the responsibility for molecular dysfunctions in DS. […] Hsa21 gene expression was found globally upregulated 1.5-fold in trisomic samples, in full agreement with a gene-dosage effect. […] The dysregulation of one or more of these genes might account for mitochondrial alterations observed in DS. […] The knowledge of molecular bases of mitochondrial dysfunction is allowing to set-up most appropriate therapeutic solutions to counteract it.

• #80 Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction – World Mitochondria Society

  https://wms-site.com/alert-on-mitochondria/849-down-syndrome-role-of-hydrogen-sulfide-overproduction-in-the-pathogenesis-of-mitochondrial-dysfunction

  Prof. Szabo will give a talk entitled „Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction” during the congress which will be held on October 29-30, 2020 in Berlin, Germany. […] An increased expression of CBS and the consequent overproduction of H2S is well documented in individuals with Down syndrome (DS). […] Two decades ago, it has been proposed that a toxic overproduction of H2S importantly contributes to the metabolic and neurological deficits associated with DS. […] The present talk will present recent data generated in human dermal fibroblasts showing that DS cells overproduce H2S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. […] Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: this results in the improvement of mitochondrial function in DS cells.

• #81 Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction – World Mitochondria Society

  https://wms-site.com/alert-on-mitochondria/849-down-syndrome-role-of-hydrogen-sulfide-overproduction-in-the-pathogenesis-of-mitochondrial-dysfunction

  Prof. Szabo will give a talk entitled „Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction” during the congress which will be held on October 29-30, 2020 in Berlin, Germany. […] An increased expression of CBS and the consequent overproduction of H2S is well documented in individuals with Down syndrome (DS). […] Two decades ago, it has been proposed that a toxic overproduction of H2S importantly contributes to the metabolic and neurological deficits associated with DS. […] The present talk will present recent data generated in human dermal fibroblasts showing that DS cells overproduce H2S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. […] Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: this results in the improvement of mitochondrial function in DS cells.

• #82 Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction – World Mitochondria Society

  https://wms-site.com/alert-on-mitochondria/849-down-syndrome-role-of-hydrogen-sulfide-overproduction-in-the-pathogenesis-of-mitochondrial-dysfunction

  Prof. Szabo will give a talk entitled „Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction” during the congress which will be held on October 29-30, 2020 in Berlin, Germany. […] An increased expression of CBS and the consequent overproduction of H2S is well documented in individuals with Down syndrome (DS). […] Two decades ago, it has been proposed that a toxic overproduction of H2S importantly contributes to the metabolic and neurological deficits associated with DS. […] The present talk will present recent data generated in human dermal fibroblasts showing that DS cells overproduce H2S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. […] Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: this results in the improvement of mitochondrial function in DS cells.

• #83 Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction – World Mitochondria Society

  https://wms-site.com/alert-on-mitochondria/849-down-syndrome-role-of-hydrogen-sulfide-overproduction-in-the-pathogenesis-of-mitochondrial-dysfunction

  Prof. Szabo will give a talk entitled „Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction” during the congress which will be held on October 29-30, 2020 in Berlin, Germany. […] An increased expression of CBS and the consequent overproduction of H2S is well documented in individuals with Down syndrome (DS). […] Two decades ago, it has been proposed that a toxic overproduction of H2S importantly contributes to the metabolic and neurological deficits associated with DS. […] The present talk will present recent data generated in human dermal fibroblasts showing that DS cells overproduce H2S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. […] Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: this results in the improvement of mitochondrial function in DS cells.

• #84 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  The key role of PGC-1 as a modulator of mitochondrial biogenesis and respiratory function suggests that therapeutic approach on mitochondrial dysfunction in DS could be based either on PGC-1 activators or on PPARg agonists, which demonstrated to attenuate mitochondrial dysfunction in AD mouse models. […] Metformin demonstrated to induce both the expression and the activity of PGC-1 and to upregulate its target genes NRF-1 and TFAM, thus promoting mitochondrial biogenesis. The drug enhanced ATP production in treated cells and improved overall mitochondrial activity.

• #85 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  The key role of PGC-1 as a modulator of mitochondrial biogenesis and respiratory function suggests that therapeutic approach on mitochondrial dysfunction in DS could be based either on PGC-1 activators or on PPARg agonists, which demonstrated to attenuate mitochondrial dysfunction in AD mouse models. […] Metformin demonstrated to induce both the expression and the activity of PGC-1 and to upregulate its target genes NRF-1 and TFAM, thus promoting mitochondrial biogenesis. The drug enhanced ATP production in treated cells and improved overall mitochondrial activity.

• #86 Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3596542/

  Elevated rates of neuronal apoptosis related to oxidative stress have been reported in DS. […] Moreover, recent research provides evidence that oxidative stress is elevated in the Ts1Cje mouse, suggesting that one or more genes trisomic in this model, likely contribute to DS-associated oxidative stress. […] Recently, it was proposed that DYRK1A contributes to DS neural phenotypes, such as impaired dendritic growth, by disturbing neuron-restrictive silencer factor (REST/NRSF) levels. […] MicroRNAs encoded by Hsa21 may also influence development of the brain; specifically trisomy of miR-155 and miR-802 has been suggested to regulate the expression of the methyl-CpG-binding-protein gene (MECP2), which is known to be important in neurodevelopment. […] DS is complex disorder and dissecting the genetic and molecular processes underlying the syndrome requires many different complementary approaches, including the study of human data and mouse and other model organisms. […] However, several recent breakthroughs have increased our understanding of the effects of Hsa21 trisomy. Combining information from studies of people with DS with the power of mouse models of trisomy has enabled genetic associations to be tested and continues to lead to the identification of genes that cause DS-associated pathology. Significant advances in basic research have been instrumental in determining the molecular mechanisms underlying these phenotypes leading to useful therapeutic interventions.

• #87 Down syndrome

  https://dermnetnz.org/topics/dermatological-manifestations-of-down-syndrome

  Down syndrome is a common genetic disorder resulting from the chromosomal abnormality, trisomy 21. […] A cell division error during early conception results in three copies of chromosome 21 instead of the usual two. The chromosomal abnormality results from nondisjunction (a lack of normal separation) during cell division as the pair of chromosomes in either the sperm or egg fail to separate. This results in a gain of an additional chromosome 21 and the occurrence of Down syndrome. […] The overexpression of the SOD gene, which regulates free radical metabolism, is located on chromosome 21, and is overexpressed as a result of trisomy 21; this leads to excess production of hydrogen peroxide, causing the release of cytotoxic hydroxyl radicals. This, in turn, causes cell-membrane lipid oxidation, altering the structure and function of the skin and involved tissues. […] Chronic skin conditions associated with Down syndrome may be related to immune insufficiency, autoimmune processes, infections and infestation-related complications, and defects of keratinisation or connective tissue.

• #88 Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3596542/

  Elevated rates of neuronal apoptosis related to oxidative stress have been reported in DS. […] Moreover, recent research provides evidence that oxidative stress is elevated in the Ts1Cje mouse, suggesting that one or more genes trisomic in this model, likely contribute to DS-associated oxidative stress. […] Recently, it was proposed that DYRK1A contributes to DS neural phenotypes, such as impaired dendritic growth, by disturbing neuron-restrictive silencer factor (REST/NRSF) levels. […] MicroRNAs encoded by Hsa21 may also influence development of the brain; specifically trisomy of miR-155 and miR-802 has been suggested to regulate the expression of the methyl-CpG-binding-protein gene (MECP2), which is known to be important in neurodevelopment. […] DS is complex disorder and dissecting the genetic and molecular processes underlying the syndrome requires many different complementary approaches, including the study of human data and mouse and other model organisms. […] However, several recent breakthroughs have increased our understanding of the effects of Hsa21 trisomy. Combining information from studies of people with DS with the power of mouse models of trisomy has enabled genetic associations to be tested and continues to lead to the identification of genes that cause DS-associated pathology. Significant advances in basic research have been instrumental in determining the molecular mechanisms underlying these phenotypes leading to useful therapeutic interventions.

• #89 Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3596542/

  Elevated rates of neuronal apoptosis related to oxidative stress have been reported in DS. […] Moreover, recent research provides evidence that oxidative stress is elevated in the Ts1Cje mouse, suggesting that one or more genes trisomic in this model, likely contribute to DS-associated oxidative stress. […] Recently, it was proposed that DYRK1A contributes to DS neural phenotypes, such as impaired dendritic growth, by disturbing neuron-restrictive silencer factor (REST/NRSF) levels. […] MicroRNAs encoded by Hsa21 may also influence development of the brain; specifically trisomy of miR-155 and miR-802 has been suggested to regulate the expression of the methyl-CpG-binding-protein gene (MECP2), which is known to be important in neurodevelopment. […] DS is complex disorder and dissecting the genetic and molecular processes underlying the syndrome requires many different complementary approaches, including the study of human data and mouse and other model organisms. […] However, several recent breakthroughs have increased our understanding of the effects of Hsa21 trisomy. Combining information from studies of people with DS with the power of mouse models of trisomy has enabled genetic associations to be tested and continues to lead to the identification of genes that cause DS-associated pathology. Significant advances in basic research have been instrumental in determining the molecular mechanisms underlying these phenotypes leading to useful therapeutic interventions.

• #90 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  Abnormal physiologic functioning affects thyroid metabolism and intestinal malabsorption. Patients with trisomy 21 have an increased risk of obesity. Frequent infections are presumably due to impaired immune responses, and the incidence of autoimmunity, including as seen in the development of hypothyroidism and rare Hashimoto thyroiditis, is increased. […] Patients with Down syndrome have decreased buffering of physiologic reactions, resulting in hypersensitivity to pilocarpine and abnormal responses on sensory-evoked electroencephalographic (EEG) tracings. Children with leukemic Down syndrome also have hyperreactivity to methotrexate. […] Decreased buffering of metabolic processes results in a predisposition to hyperuricemia and increased insulin resistance. Diabetes mellitus develops in many affected patients. Premature senescence causes cataracts and Alzheimer disease.

• #91 Down Syndrome: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/943216-overview

  Abnormal physiologic functioning affects thyroid metabolism and intestinal malabsorption. Patients with trisomy 21 have an increased risk of obesity. Frequent infections are presumably due to impaired immune responses, and the incidence of autoimmunity, including as seen in the development of hypothyroidism and rare Hashimoto thyroiditis, is increased. […] Patients with Down syndrome have decreased buffering of physiologic reactions, resulting in hypersensitivity to pilocarpine and abnormal responses on sensory-evoked electroencephalographic (EEG) tracings. Children with leukemic Down syndrome also have hyperreactivity to methotrexate. […] Decreased buffering of metabolic processes results in a predisposition to hyperuricemia and increased insulin resistance. Diabetes mellitus develops in many affected patients. Premature senescence causes cataracts and Alzheimer disease.

• #92 Down Syndrome (Trisomy 21) – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/chromosome-and-gene-abnormalities/down-syndrome-trisomy-21

  Approximately 50% of affected neonates have congenital heart disease; ventricular septal defect and atrioventricular canal defect are most common. […] Many people develop endocrinopathies, including thyroid disease (most often hypothyroidism) and diabetes. […] The aging process seems to be accelerated. […] The underlying genetic abnormality cannot be cured. […] Some congenital cardiac or gastrointestinal anomalies are repaired surgically. […] Down syndrome involves an extra chromosome 21, either a separate chromosome or a translocation onto another chromosome. […] Life expectancy is decreased primarily because of heart disease and, to a lesser degree, increased susceptibility to infections, acute myelocytic leukemia, and early-onset Alzheimer disease.

• #93 A novel mechanism underlying pathogenesis of Down syndrome | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-8-s1-o23

  Down syndrome (DS) patients unanimously develop pathologies of Alzheimers disease (AD) in their 30s or 40s. Since DS is caused by the existence of an extra copy of chromosome 21 in cells, an over-dosage of genes on chromosome 21 may play a role in the pathogenesis of DS and perhaps AD as well. […] Our identification of the role of SNX27 in synaptic function and in regulating -secretase activity and A generation establishes a new molecular mechanism for pathogenesis of both DS and AD.

• #94 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | Picower Institute

  https://picower.mit.edu/news/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-state

  Another implication of the findings is how excessive senescence among brain cells might affect people with Down syndrome later in life. The risk of Alzheimers disease is much higher at a substantially earlier age in the Down syndrome population than among people in general. […] The newly identified inclination for senescence may also accelerate Alzheimers development.

• #95 Down’s syndrome, neroinflammation, and Alzheimer neuropathogenesis

  https://uknowledge.uky.edu/physiology_facpub/13/

  Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. […] Mapping of the gene that encodes the precursor protein (APP) of the -amyloid (A) present in the A plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. […] The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer’s disease.

• #96

  https://step1.medbullets.com/evidence/23866266

  Down syndrome (DS) is the result of triplication of chromosome 21 (trisomy 21) and is the prevailing cause of mental retardation. […] Mapping of the gene that encodes the precursor protein (APP) of the -amyloid (A) present in the A plaques in both AD and DS to chromosome 21 was strong evidence that this chromosome 21 gene product was a principal neuropathogenic culprit in AD as well as DS. […] The discovery of neuroinflammatory changes, including dramatic proliferation of activated glia overexpressing a chromosome 2 gene product–the pluripotent immune cytokine interleukin-1 (IL-1)–and a chromosome 21 gene product–S100B–in the brains of fetuses, neonates, and children with DS opened the possibility that early events in Alzheimer pathogenesis were driven by cytokines. […] The specific chromosome 21 gene products and the complexity of the mechanisms they engender that give rise to the neuroinflammatory responses noted in fetal development of the DS brain and their potential as accelerators of Alzheimer neuropathogenesis in DS are topics of this review, particularly as they relate to development and propagation of neuroinflammation, the consequences of which are recognized clinically and neuropathologically as Alzheimer’s disease.

• #97 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | MIT News | Massachusetts Institute of Technology

  https://news.mit.edu/2022/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-0110

  In Down syndrome, the third copy of chromosome 21 causes a reorganization of the 3D configuration of the entire genome in a key cell type of the developing brain, a new study shows. […] The study published in Cell Stem Cell therefore establishes senescence as a potentially targetable mechanism for future treatment of Down syndrome, says Hiruy Meharena, who led the work as a Senior Alana Fellow in the Alana Down Syndrome Center at MIT and is now an assistant professor at the University of California at San Diego. […] This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome. […] The study’s finding that neural progenitor cells (NPCs), which develop into major cells in the brain including neurons, have a senescent character is remarkable and novel, says senior author Li-Huei Tsai, but it is substantiated by the team’s extensive work to elucidate the underlying mechanism of the effects of abnormal chromosome number, or aneuploidy, within the nucleus of the cells.

• #98 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | Picower Institute

  https://picower.mit.edu/news/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-state

  Extra chromosome alters chromosomal conformation and DNA accessibility across the whole genome in neural progenitor cells, disrupting gene transcription and cell functions much like in cellular aging […] In Down syndrome, the third copy of chromosome 21 causes a reorganization of the 3D configuration of the entire genome in a key cell type of the developing brain, a new study shows. […] The resulting disruption of gene transcription and cell function are so similar to those seen in cellular aging, or senescence, that the scientists leading the study found they could use anti-senescence drugs to correct them in cell cultures. […] There is a cell-type specific genome-wide disruption that is independent of the gene dosage response, Meharena said. Its a very similar phenomenon to whats observed in senescence. This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome.

• #99 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | MIT News | Massachusetts Institute of Technology

  https://news.mit.edu/2022/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-0110

  In Down syndrome, the third copy of chromosome 21 causes a reorganization of the 3D configuration of the entire genome in a key cell type of the developing brain, a new study shows. […] The study published in Cell Stem Cell therefore establishes senescence as a potentially targetable mechanism for future treatment of Down syndrome, says Hiruy Meharena, who led the work as a Senior Alana Fellow in the Alana Down Syndrome Center at MIT and is now an assistant professor at the University of California at San Diego. […] This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome. […] The study’s finding that neural progenitor cells (NPCs), which develop into major cells in the brain including neurons, have a senescent character is remarkable and novel, says senior author Li-Huei Tsai, but it is substantiated by the team’s extensive work to elucidate the underlying mechanism of the effects of abnormal chromosome number, or aneuploidy, within the nucleus of the cells.

• #100 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | Picower Institute

  https://picower.mit.edu/news/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-state

  Extra chromosome alters chromosomal conformation and DNA accessibility across the whole genome in neural progenitor cells, disrupting gene transcription and cell functions much like in cellular aging […] In Down syndrome, the third copy of chromosome 21 causes a reorganization of the 3D configuration of the entire genome in a key cell type of the developing brain, a new study shows. […] The resulting disruption of gene transcription and cell function are so similar to those seen in cellular aging, or senescence, that the scientists leading the study found they could use anti-senescence drugs to correct them in cell cultures. […] There is a cell-type specific genome-wide disruption that is independent of the gene dosage response, Meharena said. Its a very similar phenomenon to whats observed in senescence. This suggests that excessive senescence in the developing brain induced by the third copy of chromosome 21 could be a key reason for the neurodevelopmental abnormalities seen in Down syndrome.

• #101 In Down syndrome cells, genome-wide disruptions mimic a senescence-like state | Picower Institute

  https://picower.mit.edu/news/down-syndrome-cells-genome-wide-disruptions-mimic-senescence-state

  Another implication of the findings is how excessive senescence among brain cells might affect people with Down syndrome later in life. The risk of Alzheimers disease is much higher at a substantially earlier age in the Down syndrome population than among people in general. […] The newly identified inclination for senescence may also accelerate Alzheimers development.

• #102 Down syndrome and the molecular pathogenesis resulting from trisomy of human chromosome 21

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3596542/

  Elevated rates of neuronal apoptosis related to oxidative stress have been reported in DS. […] Moreover, recent research provides evidence that oxidative stress is elevated in the Ts1Cje mouse, suggesting that one or more genes trisomic in this model, likely contribute to DS-associated oxidative stress. […] Recently, it was proposed that DYRK1A contributes to DS neural phenotypes, such as impaired dendritic growth, by disturbing neuron-restrictive silencer factor (REST/NRSF) levels. […] MicroRNAs encoded by Hsa21 may also influence development of the brain; specifically trisomy of miR-155 and miR-802 has been suggested to regulate the expression of the methyl-CpG-binding-protein gene (MECP2), which is known to be important in neurodevelopment. […] DS is complex disorder and dissecting the genetic and molecular processes underlying the syndrome requires many different complementary approaches, including the study of human data and mouse and other model organisms. […] However, several recent breakthroughs have increased our understanding of the effects of Hsa21 trisomy. Combining information from studies of people with DS with the power of mouse models of trisomy has enabled genetic associations to be tested and continues to lead to the identification of genes that cause DS-associated pathology. Significant advances in basic research have been instrumental in determining the molecular mechanisms underlying these phenotypes leading to useful therapeutic interventions.

• #103 Trisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro | Nature Communications

  https://www.nature.com/articles/s41467-018-07630-y

  We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. […] Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. […] This study demonstrates proof-of-principle for this epigenetic-based strategy to investigate, and potentially mitigate, DS developmental pathologies. […] A priori, it cannot be assumed that XIST-mediated transcriptional repression would be sufficiently robust to correct cell pathogenesis, even in cells that still must carry the physical presence of the extra chromosome 21. […] Results show that trisomy 21 over-expression promotes excess CD43+ progenitors, but not the earlier CD34+ hemogenic endothelium (HE) population.

• #104 Trisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro | Nature Communications

  https://www.nature.com/articles/s41467-018-07630-y

  We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. […] Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. […] This study demonstrates proof-of-principle for this epigenetic-based strategy to investigate, and potentially mitigate, DS developmental pathologies. […] A priori, it cannot be assumed that XIST-mediated transcriptional repression would be sufficiently robust to correct cell pathogenesis, even in cells that still must carry the physical presence of the extra chromosome 21. […] Results show that trisomy 21 over-expression promotes excess CD43+ progenitors, but not the earlier CD34+ hemogenic endothelium (HE) population.

• #105 Trisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro | Nature Communications

  https://www.nature.com/articles/s41467-018-07630-y

  We previously demonstrated that an integrated XIST transgene can broadly repress one chromosome 21 in Down syndrome (DS) pluripotent cells. […] Here we address whether trisomy-silencing can normalize cell function and development sufficiently to correct cell pathogenesis, tested in an in vitro model of human fetal hematopoiesis, for which DS cellular phenotypes are best known. […] This study demonstrates proof-of-principle for this epigenetic-based strategy to investigate, and potentially mitigate, DS developmental pathologies. […] A priori, it cannot be assumed that XIST-mediated transcriptional repression would be sufficiently robust to correct cell pathogenesis, even in cells that still must carry the physical presence of the extra chromosome 21. […] Results show that trisomy 21 over-expression promotes excess CD43+ progenitors, but not the earlier CD34+ hemogenic endothelium (HE) population.

• #106 Trisomy silencing by XIST normalizes Down syndrome cell pathogenesis demonstrated for hematopoietic defects in vitro | Nature Communications

  https://www.nature.com/articles/s41467-018-07630-y

  Understanding how trisomy 21 leads to cell pathology will be important for development of traditional therapeutics for DS, and our results provide substantial new insights into this. […] Therefore, these results provide the first critical demonstration that cellular phenotype can be normalized or greatly mitigated by XIST RNA-mediated chromosome silencing. […] Our results demonstrate that the IGF-related effects of trisomy 21 are evident in non-leukemic hematopoietic progenitor cells (prior to GATA1s mutation). […] Our results do not rule out that GATA1s mutations also contribute as Klusmann et al. suggested, but these authors also acknowledged that trisomy 21 itself might enhance IGF signaling. […] Hence, this inducible chromosome silencing provides a valuable experimental approach to determine the most direct effects of trisomy 21 on cell function and development, important for traditional drug therapeutics.

• #107 Protein-protein interaction discovery unveils Down syndrome’s molecular mechanism potential | ScienceDaily

  https://www.sciencedaily.com/releases/2023/12/231219124438.htm

  Down syndrome, a congenital disorder stemming from abnormal cell division and differentiation, is most common in newborns fated to neurodevelopmental delays and other health complications. […] The genetic defect causes the dysfunction of the protein kinase DYRK1A, which is encoded on chromosome 21 and is deeply associated with both Down syndrome and autism spectrum disorder. DYRK1A has attracted attention as a target molecule for treating various diseases, but specific cellular mechanisms regulating the enzyme DYRK1A have yet to be made clear. […] Now, researchers at Kyoto University have identified the FAM53C protein and its DYRK1A-inhibiting effect that keeps the protein kinase inactive inside the cytoplasm. […] DYRK1A controls many biological functions, including the development and function of the nervous system. At the cellular level, this critical protein phosphorylates various other proteins in the cytoplasm and nucleus to regulate the cell cycle, cell differentiation, cytoskeletal formation, and DNA damage response.

• #108 Protein-protein interaction discovery unveils Down syndrome’s molecular mechanism potential | ScienceDaily

  https://www.sciencedaily.com/releases/2023/12/231219124438.htm

  Down syndrome, a congenital disorder stemming from abnormal cell division and differentiation, is most common in newborns fated to neurodevelopmental delays and other health complications. […] The genetic defect causes the dysfunction of the protein kinase DYRK1A, which is encoded on chromosome 21 and is deeply associated with both Down syndrome and autism spectrum disorder. DYRK1A has attracted attention as a target molecule for treating various diseases, but specific cellular mechanisms regulating the enzyme DYRK1A have yet to be made clear. […] Now, researchers at Kyoto University have identified the FAM53C protein and its DYRK1A-inhibiting effect that keeps the protein kinase inactive inside the cytoplasm. […] DYRK1A controls many biological functions, including the development and function of the nervous system. At the cellular level, this critical protein phosphorylates various other proteins in the cytoplasm and nucleus to regulate the cell cycle, cell differentiation, cytoskeletal formation, and DNA damage response.

• #109 Protein-protein interaction discovery unveils Down syndrome’s molecular mechanism potential | ScienceDaily

  https://www.sciencedaily.com/releases/2023/12/231219124438.htm

  Down syndrome, a congenital disorder stemming from abnormal cell division and differentiation, is most common in newborns fated to neurodevelopmental delays and other health complications. […] The genetic defect causes the dysfunction of the protein kinase DYRK1A, which is encoded on chromosome 21 and is deeply associated with both Down syndrome and autism spectrum disorder. DYRK1A has attracted attention as a target molecule for treating various diseases, but specific cellular mechanisms regulating the enzyme DYRK1A have yet to be made clear. […] Now, researchers at Kyoto University have identified the FAM53C protein and its DYRK1A-inhibiting effect that keeps the protein kinase inactive inside the cytoplasm. […] DYRK1A controls many biological functions, including the development and function of the nervous system. At the cellular level, this critical protein phosphorylates various other proteins in the cytoplasm and nucleus to regulate the cell cycle, cell differentiation, cytoskeletal formation, and DNA damage response.

• #110 Protein-protein interaction discovery unveils Down syndrome’s molecular mechanism potential | ScienceDaily

  https://www.sciencedaily.com/releases/2023/12/231219124438.htm

  Notably, the structurally flexible FAM53C protein binds directly to a region of DYRK1A responsible for protein phosphorylation. This interaction reduces DYRK1A’s kinase activity, securely anchoring DYRK1A within the cytoplasm but outside the cell nucleus, as in normal brain tissue. […] „The FAM53C-mediated regulation of the protein kinase activity may significantly impact gene expression regulation caused by normal and aberrant levels of DYRK1A, giving us many potential clinical insights,” suggests Miyata.

• #111 Protein-protein interaction discovery unveils Down syndrome’s molecular mechanism potential | ScienceDaily

  https://www.sciencedaily.com/releases/2023/12/231219124438.htm

  Notably, the structurally flexible FAM53C protein binds directly to a region of DYRK1A responsible for protein phosphorylation. This interaction reduces DYRK1A’s kinase activity, securely anchoring DYRK1A within the cytoplasm but outside the cell nucleus, as in normal brain tissue. […] „The FAM53C-mediated regulation of the protein kinase activity may significantly impact gene expression regulation caused by normal and aberrant levels of DYRK1A, giving us many potential clinical insights,” suggests Miyata.

• #112 Scientists Discover Mechanism Affecting Heart Development in Down Syndrome | Global Down Syndrome Foundation

  https://www.globaldownsyndrome.org/scientists-discover-mechanism-affecting-heart-development-in-down-syndrome/

  Unveiling this sequence of occurrences sheds light on possible approaches to mitigate abnormal heart development in Down syndrome by reducing interferon signaling and/or enhancing Wnt signaling. […] These findings hold great significance as they propose a prospective pharmacological approach for prenatal intervention in mitigating one of the severe consequences of trisomy 21. […] These findings contribute to the expanding body of evidence highlighting the detrimental consequences of excessive interferon activity in Down syndrome, even in the initial phases of embryonic development. […] The outcomes further endorse the notion that several distinctive features of Down syndrome stem from persistent immune system dysregulation throughout life, and that reinstating immune equilibrium could yield therapeutic advantages.

• #113 Scientists Discover Mechanism Affecting Heart Development in Down Syndrome | Global Down Syndrome Foundation

  https://www.globaldownsyndrome.org/scientists-discover-mechanism-affecting-heart-development-in-down-syndrome/

  Unveiling this sequence of occurrences sheds light on possible approaches to mitigate abnormal heart development in Down syndrome by reducing interferon signaling and/or enhancing Wnt signaling. […] These findings hold great significance as they propose a prospective pharmacological approach for prenatal intervention in mitigating one of the severe consequences of trisomy 21. […] These findings contribute to the expanding body of evidence highlighting the detrimental consequences of excessive interferon activity in Down syndrome, even in the initial phases of embryonic development. […] The outcomes further endorse the notion that several distinctive features of Down syndrome stem from persistent immune system dysregulation throughout life, and that reinstating immune equilibrium could yield therapeutic advantages.

• #114 Uncovering the mechanisms behind autoimmunity in Down’s syndrome

  https://frontlinegenomics.com/uncovering-the-mechanisms-behind-autoimmunity-in-downs-syndrome/

  Consequently, the team chose to further investigate the presence of CD11c+ cells in individuals with Down’s syndrome. […] However, as there is an increased proportion of CD11c+ cells in individuals with Down’s syndrome, this would imply a heightened level of CD11c+-derived autoimmunity. […] These two features led the researchers to the conclusion that cytokine and T-cell mediated activation of CD11c+ cells was likely a major driver of increased inflammatory responses and autoimmunity in those with Down’s syndrome. […] With an understanding of the underlying cause, there is now potential for autoimmune conditions in those with Down’s syndrome to be addressed at the source, rather than simply treating the symptoms. […] Lead author Dusan Bugnovich stated: “Available drugs such as tocilizumab and a variety of JAK inhibitors could potentially tame this inflammation.”

• #115 Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches | IntechOpen

  https://www.intechopen.com/chapters/57817

  The key role of PGC-1 as a modulator of mitochondrial biogenesis and respiratory function suggests that therapeutic approach on mitochondrial dysfunction in DS could be based either on PGC-1 activators or on PPARg agonists, which demonstrated to attenuate mitochondrial dysfunction in AD mouse models. […] Metformin demonstrated to induce both the expression and the activity of PGC-1 and to upregulate its target genes NRF-1 and TFAM, thus promoting mitochondrial biogenesis. The drug enhanced ATP production in treated cells and improved overall mitochondrial activity.

• #116 Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction – World Mitochondria Society

  https://wms-site.com/alert-on-mitochondria/849-down-syndrome-role-of-hydrogen-sulfide-overproduction-in-the-pathogenesis-of-mitochondrial-dysfunction

  Prof. Szabo will give a talk entitled „Down Syndrome: Role of hydrogen sulfide overproduction in the pathogenesis of mitochondrial dysfunction” during the congress which will be held on October 29-30, 2020 in Berlin, Germany. […] An increased expression of CBS and the consequent overproduction of H2S is well documented in individuals with Down syndrome (DS). […] Two decades ago, it has been proposed that a toxic overproduction of H2S importantly contributes to the metabolic and neurological deficits associated with DS. […] The present talk will present recent data generated in human dermal fibroblasts showing that DS cells overproduce H2S, which, in turn, suppresses mitochondrial Complex IV activity and impairs mitochondrial oxygen consumption and ATP generation. […] Therapeutic CBS inhibition lifts the tonic (and reversible) suppression of Complex IV: this results in the improvement of mitochondrial function in DS cells.

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