Materiały źródłowe

• #1 Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

  https://www.mdpi.com/2073-4409/10/5/1157

  Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder (estimated prevalence of 1 in 18–20 million people) caused by a mutation in the LMNA gene that provokes accelerated aging and premature death. […] Progerin is expressed in most differentiated cells and induces multiple cellular and physiological anomalies, including defects in nuclear morphology, chromatin disorganization, elevated DNA damage, impaired stem cell maintenance and differentiation, metabolic alterations, autophagy deregulation, and systemic inflammation. […] The extreme rarity of HGPS hinders systematic cardiovascular examination of patients, because the very few HGPS patients are spread around the world, may be diagnosed at different ages, and have very different access to primary and specialized care.

• #2 Hutchinson-Gilford Progeria Syndrome: An Overview of the Molecular Mechanism, Pathophysiology and Therapeutic Approach – PubMed

  https://pubmed.ncbi.nlm.nih.gov/33655857/

  Lamin A/C encoded by the LMNA gene is an essential component for maintaining the nuclear structure. […] HGPS is an immensely uncommon, deadly, metameric ill-timed laminopathies caused by the abnormal splicing of the LMNA gene and production of an aberrant protein known as progerin. […] Due to the production of progerin, an abnormal protein leads to an abnormality in nuclear structure, defects in DNA repair, shortening of telomere, and impairment in gene regulation which ultimately results in aging in the early stage of life. […] a proper understanding of the molecular mechanism of this disease will help to develop a more appropriate treatment which makes it an emerging area of research.

• #3 Hutchinson-Gilford Progeria Syndrome | SpringerLink

  https://link.springer.com/10.1007/978-3-030-22009-9_53

  Hutchinson-Gilford progeria syndrome (HGPS), often referred to as progeria, is an extremely rare autosomal dominant neonatal condition. […] The genetic change responsible for HGPS is a sporadic point mutation that leads to a cryptic splice site in the lamin A gene, LMNA. […] Lamin A is an intermediate filament in the nuclear lamina and confers structural integrity to the nuclear envelope. […] Progeria is a segmental aging syndrome, developing many but not all the characteristics of premature aging. […] Hutchinson-Gilford progeria syndrome: a premature aging disease caused by LMNA gene mutations. […] Progerin-induced replication stress facilitates premature senescence in Hutchinson-Gilford progeria syndrome.

• #4 Hutchinson-Gilford progeria syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/hutchinson-gilford-progeria-syndrome/

  Hutchinson-Gilford progeria syndrome is a genetic condition characterized by the dramatic, rapid appearance of aging beginning in childhood. […] Mutations in the LMNA gene cause Hutchinson-Gilford progeria syndrome. The LMNA gene provides instructions for making a protein called lamin A. This protein plays an important role in determining the shape of the nucleus within cells. It is an essential scaffolding (supporting) component of the nuclear envelope, which is the membrane that surrounds the nucleus. Mutations that cause Hutchinson-Gilford progeria syndrome result in the production of an abnormal version of the lamin A protein. The altered protein makes the nuclear envelope unstable and progressively damages the nucleus, making cells more likely to die prematurely. Researchers are working to determine how these changes lead to the characteristic features of Hutchinson-Gilford progeria syndrome.

• #5 Hutchinson-Gilford Progeria Syndrome | IntechOpen

  https://www.intechopen.com/chapters/41856

  Hutchinson-Gilford Progeria Syndrome (HGPS) is a lethal congenital disorder, characterised by premature appearance of accelerated ageing in children. Approximately 90% of HGPS patients have an identical mutation in paternal allele of the LMNA gene a substitution of cytosine to thymine at nucleotide 1824, c.1824CT. Although apparently a silent mutation (that is, no change in the amino acid, G608G), it causes aberrant mRNA splicing, which leads to the production of a truncated and partially processed pre-lamin A protein called progerin. Accumulation of progerin is thought to underlie the pathophysiology of HGPS. […] The first evidence for changes of nuclear architecture during the normal ageing process came from work in C. elegans. In this study, the authors demonstrated that nuclear defects accumulate during ageing and suggested that HGPS may be a result of increased rate of the normal ageing process.

• #6 Progeria – Wikipedia

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

  Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered to be a point mutation in position 1824 of the LMNA gene, which replaces a cytosine with thymine. This mutation creates a 5′ cryptic splice site within exon 11, resulting in a shorter than normal mRNA transcript. When this shorter mRNA is translated into protein, it produces an abnormal variant of the prelamin A protein, referred to as progerin. Progerin’s farnesyl group cannot be removed because the ZMPSTE24 cleavage site is lacking from progerin, so the abnormal protein is permanently attached to the nuclear rim. One result is that the nuclear lamina does not provide the nuclear envelope with enough structural support, causing it to take on an abnormal shape.

• #7 Studying the Molecular Mechanism of Post-Translational Modification of Lamin A in Hutchinson-Gilford Progeria Syndrome

  https://www.lakeforest.edu/news/studying-the-molecular-mechanism-of-post-translational-modification-of-lamin-a-in-hutchinson-gilford-progeria-syndrome

  Hutchinson-Gilford Progeria Syndrome (HGPS) is a genetic condition that presents itself as premature aging. It is caused by a point mutation in exon eleven of the LMNA gene. This gene is responsible for producing lamin A and lamin C proteins. The point mutation is a silent mutation that causes the splicing pattern of LMNA to be altered resulting in a mutant protein called progerin to form. The build-up of this protein causes HGPS. […] FTIs help alleviate the symptoms of afflicted children and hopefully can be utilized in the future as a cure. […] The mutation is classified as a de novo mutation where the mutation is received without either parent having the point mutation. However, it is unclear when this mutation occurs. HGPS is an autosomal dominant condition, thus only one mutant LMNA allele is necessary for the condition. The mutation is a silent mutation in exon eleven of the LMNA gene on chromosome one. A silent mutation is a point mutation in the genome, but the amino acid sequence is not altered. Therefore, change of a cytosine to a thymine in exon eleven results in glycine remaining as the amino acid in the primary structure of lamin A. However, the silent mutation alters the splicing pattern of the LMNA gene where an additional gene product is produced known as a progerin. The activation of this splice variant results in the deletion of fifty amino acids from the C-terminal end of the protein. This causes an abnormal immature lamin A protein to be produced since the protein cannot undergo post-translation modifications due to the fifty amino acid deletion. Therefore, the silent mutation prevents the proper synthesis of lamin A since the mature protein is unable to be produced.

• #8 Molecular ageing in progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model | Immunity & Ageing | Full Text

  https://immunityageing.biomedcentral.com/articles/10.1186/1742-4933-6-4

  HGPS is related to a mutation in the LMNA gene or in ZMPSTE2 that codes for a metalloproteinase specifically involved in the post-translational proteolytic processing of prelamin A to mature lamin A, which is responsible for scaffolding and organizing the nuclear envelope surface. […] The inheritance pattern in progeria syndrome is autosomal dominant (or less frequently recessive when involving the ZMPSTE24 gene). All subjects with HGPS have the disease as result of a de novo mutation (the most common mutation is p.G608G), as their parents are not affected. This mutation causes aberrant splicing in exon 11 and the deletion of 50 residues close to the C terminus of lamin A, including the second ZMPSTE24 cleavage site. This deletion prevents complete processing of prelamin A, resulting in the accumulation of a farnesylated lamin A, known as progerin.

• #9 Studying the Molecular Mechanism of Post-Translational Modification of Lamin A in Hutchinson-Gilford Progeria Syndrome

  https://www.lakeforest.edu/news/studying-the-molecular-mechanism-of-post-translational-modification-of-lamin-a-in-hutchinson-gilford-progeria-syndrome

  Hutchinson-Gilford Progeria Syndrome (HGPS) is a genetic condition that presents itself as premature aging. It is caused by a point mutation in exon eleven of the LMNA gene. This gene is responsible for producing lamin A and lamin C proteins. The point mutation is a silent mutation that causes the splicing pattern of LMNA to be altered resulting in a mutant protein called progerin to form. The build-up of this protein causes HGPS. […] FTIs help alleviate the symptoms of afflicted children and hopefully can be utilized in the future as a cure. […] The mutation is classified as a de novo mutation where the mutation is received without either parent having the point mutation. However, it is unclear when this mutation occurs. HGPS is an autosomal dominant condition, thus only one mutant LMNA allele is necessary for the condition. The mutation is a silent mutation in exon eleven of the LMNA gene on chromosome one. A silent mutation is a point mutation in the genome, but the amino acid sequence is not altered. Therefore, change of a cytosine to a thymine in exon eleven results in glycine remaining as the amino acid in the primary structure of lamin A. However, the silent mutation alters the splicing pattern of the LMNA gene where an additional gene product is produced known as a progerin. The activation of this splice variant results in the deletion of fifty amino acids from the C-terminal end of the protein. This causes an abnormal immature lamin A protein to be produced since the protein cannot undergo post-translation modifications due to the fifty amino acid deletion. Therefore, the silent mutation prevents the proper synthesis of lamin A since the mature protein is unable to be produced.

• #10 Hutchinson-Gilford Progeria Syndrome: Pathophysiology and Possible Treatments

  https://touroscholar.touro.edu/sjlcas/vol7/iss2/9/

  Named after the two scientists who independently described the condition, Hutchinson-Gilford Progeria Syndrome (HGPS) occurs due to a mutation in the LMNA gene that codes for Lamin A, a filament protein that acts to form the nuclear lamina in the cell nucleus. This mutation is a single C-to-T substitution at nucleotide 1824 of the LMNA gene. As a result of this mutation, an abnormal protein named 'progerin’ is synthesized instead of Lamin A, causing the nuclear membrane to be malformed. […] Since protein farnesylation is needed to target progerin to the nuclear rim, farnesyltransferase inhibitor has been proposed as a form of treatment that could reduce the occurrence of misshapen nuclei and alleviate HGPS symptoms.

• #11 Studying the Molecular Mechanism of Post-Translational Modification of Lamin A in Hutchinson-Gilford Progeria Syndrome

  https://www.lakeforest.edu/news/studying-the-molecular-mechanism-of-post-translational-modification-of-lamin-a-in-hutchinson-gilford-progeria-syndrome

  Four post-translational steps are required to produce mature lamin A. Immature lamin A is called pre-lamin A. First, a farnesyl group is added on to a cysteine containing motif on the C-terminal end of the protein. Once the farnesyl group is added to the cysteine, the three C-terminal amino acids are cleaved so cysteine is the C-terminal amino acid. The farnesyl group at the C-terminal end binds to the nuclear envelope thus anchoring lamin A to the nuclear envelope as well. A farnesylation reaction is a type of alkylation where a fifteen carbon group, a farnesyl group, is added to a cysteine residue in a protein. This group acts as a hydrophobic tail facilitating the binding of lamin A to the non-polar nuclear membrane. Metallopeptidase Zmpste24, an endoprotease, removes an eighteen amino acid peptide from the C-terminal end. This removes the farnesyl group from pre-lamin A, releasing lamin A from the nuclear membrane. Once these modifications occur, a mature lamin A is produced. However, when an individual receives the silent mutation that causes HGPS, pre-lamin A has a fifty amino acid deletion near the C-terminal end of the protein, which alters the structure of the protein such that metallopeptidase Zmpste24 is unable to bind to pre-lamin A to cleave the protein and remove the farnesyl group. Thus, pre-lamin A remains bound to the nuclear membrane and is intercalated into the inner nuclear membrane, which over time disrupts the structure of the nucleus due to the additional stress added to the nuclear membrane from the accumulation of progerin.

• #12 Hutchinson-Gilford Progeria Syndrome | IntechOpen

  https://www.intechopen.com/chapters/41856

  The genetic basis for HGPS was unknown until it was found to be a single nucleotide mutation on the paternal allele with autosomal-dominant expression. […] This mutation is located in exon 11 of LMNA gene and results in increased activation of the cryptic splice donor site, splicing the LMNA gene at 5 nucleotides upstream of the mutation, leading to accumulation of aberrant mRNA transcript, missing 150 nucleotides from normal pre-lamin A. This improperly processed protein in HGPS is thought to underlie the progression of the disease phenotype. […] In HGPS, the first 3 steps of post-translational maturation can be performed (that is, farnesylation, cleavage, and methylation), while the fourth processing step cannot be completed as the G608G mutation eliminates the second cleavage site recognised by ZMPSTE24 of pre-lamin A resulting a permanently farnesylated form of progerin.

• #13

  https://openarchive.ki.se/articles/thesis/Defining_the_role_of_CAAX_protein_proteolysis_and_methylation_in_the_pathogenesis_and_treatment_of_progeria/26894461

  Hutchinson-Gilford progeria syndrome (HGPS) is a rare childhood disease characterized by failure to thrive, bone abnormalities, hair loss, and a shortened life span due to cardiovascular disease, and nuclear shape abnormalities in cultured cells. HGPS is caused by de-novo mutations in LMNA, the gene encoding prelamin A. Lamin A is produced from prelamin A following three modifications at a carboxyl-terminal CAAX motif: farnesylation of the cysteine by farnesyltransferase (FTase); release of the AAX by RAS-converting enzyme 1 (RCE1); and methylation of the farnesylcysteine residue by isoprenylcysteine carboxyl methyltransferase (ICMT); mature lamin A is subsequently produced by proteolytic removal of the last 15 amino acids (including the farnesylcysteine residue) by Zinc metalloproteinase Ste24 homologue (ZMPSTE24).

• #14 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  Progerin seems to be produced and accumulated in small quantities in wild-type fibroblasts. […] Progerin-dependent mechanisms play a role in natural aging, and the excessive activity of these mechanisms causes premature aging in HGPS. […] Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. […] Progerin acts as a dominant factor that directly and quickly disturbs the nuclear morphology. […] The permanent farnesylation of progerin has been proposed to be one of the leading causes of HGPS phenotype. […] Progerin could impact the VDR gene epigenetic status, leading to its repression, thus contributing to HGPS phenotype.

• #15 Studying the Molecular Mechanism of Post-Translational Modification of Lamin A in Hutchinson-Gilford Progeria Syndrome

  https://www.lakeforest.edu/news/studying-the-molecular-mechanism-of-post-translational-modification-of-lamin-a-in-hutchinson-gilford-progeria-syndrome

  Four post-translational steps are required to produce mature lamin A. Immature lamin A is called pre-lamin A. First, a farnesyl group is added on to a cysteine containing motif on the C-terminal end of the protein. Once the farnesyl group is added to the cysteine, the three C-terminal amino acids are cleaved so cysteine is the C-terminal amino acid. The farnesyl group at the C-terminal end binds to the nuclear envelope thus anchoring lamin A to the nuclear envelope as well. A farnesylation reaction is a type of alkylation where a fifteen carbon group, a farnesyl group, is added to a cysteine residue in a protein. This group acts as a hydrophobic tail facilitating the binding of lamin A to the non-polar nuclear membrane. Metallopeptidase Zmpste24, an endoprotease, removes an eighteen amino acid peptide from the C-terminal end. This removes the farnesyl group from pre-lamin A, releasing lamin A from the nuclear membrane. Once these modifications occur, a mature lamin A is produced. However, when an individual receives the silent mutation that causes HGPS, pre-lamin A has a fifty amino acid deletion near the C-terminal end of the protein, which alters the structure of the protein such that metallopeptidase Zmpste24 is unable to bind to pre-lamin A to cleave the protein and remove the farnesyl group. Thus, pre-lamin A remains bound to the nuclear membrane and is intercalated into the inner nuclear membrane, which over time disrupts the structure of the nucleus due to the additional stress added to the nuclear membrane from the accumulation of progerin.

• #16 Studying the Molecular Mechanism of Post-Translational Modification of Lamin A in Hutchinson-Gilford Progeria Syndrome

  https://www.lakeforest.edu/news/studying-the-molecular-mechanism-of-post-translational-modification-of-lamin-a-in-hutchinson-gilford-progeria-syndrome

  Four post-translational steps are required to produce mature lamin A. Immature lamin A is called pre-lamin A. First, a farnesyl group is added on to a cysteine containing motif on the C-terminal end of the protein. Once the farnesyl group is added to the cysteine, the three C-terminal amino acids are cleaved so cysteine is the C-terminal amino acid. The farnesyl group at the C-terminal end binds to the nuclear envelope thus anchoring lamin A to the nuclear envelope as well. A farnesylation reaction is a type of alkylation where a fifteen carbon group, a farnesyl group, is added to a cysteine residue in a protein. This group acts as a hydrophobic tail facilitating the binding of lamin A to the non-polar nuclear membrane. Metallopeptidase Zmpste24, an endoprotease, removes an eighteen amino acid peptide from the C-terminal end. This removes the farnesyl group from pre-lamin A, releasing lamin A from the nuclear membrane. Once these modifications occur, a mature lamin A is produced. However, when an individual receives the silent mutation that causes HGPS, pre-lamin A has a fifty amino acid deletion near the C-terminal end of the protein, which alters the structure of the protein such that metallopeptidase Zmpste24 is unable to bind to pre-lamin A to cleave the protein and remove the farnesyl group. Thus, pre-lamin A remains bound to the nuclear membrane and is intercalated into the inner nuclear membrane, which over time disrupts the structure of the nucleus due to the additional stress added to the nuclear membrane from the accumulation of progerin.

• #17 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  Progerin seems to be produced and accumulated in small quantities in wild-type fibroblasts. […] Progerin-dependent mechanisms play a role in natural aging, and the excessive activity of these mechanisms causes premature aging in HGPS. […] Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. […] Progerin acts as a dominant factor that directly and quickly disturbs the nuclear morphology. […] The permanent farnesylation of progerin has been proposed to be one of the leading causes of HGPS phenotype. […] Progerin could impact the VDR gene epigenetic status, leading to its repression, thus contributing to HGPS phenotype.

• #18

  https://omim.org/entry/176670

  A number sign (#) is used with this entry because both classic infantile-onset and later childhood-onset Hutchinson-Gilford progeria syndrome (HGPS) are caused by de novo heterozygous mutation in the lamin A gene (LMNA; 150330) on chromosome 1q22. […] By light and electron microscopy of fibroblasts from HGPS patients carrying the 1824C-T mutation, Goldman et al. (2004) found significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores. These structural defects worsened as the HGPS cells aged in culture, and their severity correlated with an apparent accumulation of mutant protein, which Goldman et al. (2004) designated LA delta-50. Goldman et al. (2004) concluded that expression of LA delta-50 has an age-dependent, cumulative, and ultimately devastating effect on nuclear architecture and function that is responsible for premature aging in HGPS patients.

• #19 Progeria – Wikipedia

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

  Progeria is a specific type of progeroid syndrome, also known as Hutchinson-Gilford syndrome or Hutchinson-Gilford progeroid syndrome (HGPS). A single gene mutation is responsible for causing progeria. The affected gene, known as lamin A (LMNA), makes a protein necessary for holding the cell nucleus together. When this gene mutates, an abnormal form of lamin A protein called progerin is produced. […] HGPS is caused by mutations that weaken the structure of the cell nucleus, making normal cell division difficult. The histone mark H4K20me3 is involved and caused by de novo mutations that occur in a gene that encodes lamin A. Lamin A is made but is not processed properly. This poor processing creates an abnormal nuclear morphology and disorganized heterochromatin. Patients also do not have appropriate DNA repair, and they also have increased genomic instability.

• #20 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  Progerin accumulation at the nuclear periphery activates the NFB signaling pathway, possibly contributing to systemic inflammation inherent in aging (inflammaging). […] Progerin seems to compromise the proper localization of SIRT1 and SIRT6 known to play important roles in mammalian aging. […] Progerin-induced changes in ING1 distribution could globally affect DNA methylation. […] Progerin may be involved both in tumor protection and metabolic adaptations. […] The accelerated aging phenotype in HGPS is a consequence of progerin-impaired nuclear envelope structure that might lead to nuclear leakiness and disruption of nucleocytoplasmic compartmentalization.

• #21 The Molecular and Cellular Basis of Hutchinson–Gilford Progeria Syndrome and Potential Treatments

  https://www.mdpi.com/2073-4425/14/3/602

  In HGPS, the point mutation 1824 (C>T) is a silent base substitution (Gly608Gly or G608G). However, it produces an active cryptic splice donor site. […] The initial steps (1) to (3) of the post-translational modifications are the same for the mutated prelamin A. However, the final cleavage step does not occur due to the absence of the ZMPSTE24-endoproteolytic site in the missing 50 amino acids; thus, progerin is generated instead of the mature lamin A. […] The progerin is permanently farnesylated and is anchored to the nuclear membrane. Consequently, progerin induces nuclear abnormalities, such as lobulation. […] HGPS fibroblasts have been consistently observed to have increased DNA damage response (DDR) markers (53BP1 and γH2AX foci). Therefore, the DDR is persistently activated, with increased levels of phosphorylated Chk1 and Chk2 (pChk1 and pChk2), two important downstream DDR kinases, as well as ATM and ATR, two important upstream DDR kinases.

• #22 The Molecular and Cellular Basis of Hutchinson–Gilford Progeria Syndrome and Potential Treatments

  https://www.mdpi.com/2073-4425/14/3/602

  The activation of these DDR kinases induces a senescent state. […] The overall relationship between the progerin phenotype and the effect on telomere characteristics still requires further explanation. […] Taken together, these data suggest that a central factor in the molecular cause of HGPS could be the dysfunction at the LADs. However, the extent of its importance is yet to be experimentally determined.

• #23 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  Progerin accumulation at the nuclear periphery activates the NFB signaling pathway, possibly contributing to systemic inflammation inherent in aging (inflammaging). […] Progerin seems to compromise the proper localization of SIRT1 and SIRT6 known to play important roles in mammalian aging. […] Progerin-induced changes in ING1 distribution could globally affect DNA methylation. […] Progerin may be involved both in tumor protection and metabolic adaptations. […] The accelerated aging phenotype in HGPS is a consequence of progerin-impaired nuclear envelope structure that might lead to nuclear leakiness and disruption of nucleocytoplasmic compartmentalization.

• #24 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  Progerin accumulation at the nuclear periphery activates the NFB signaling pathway, possibly contributing to systemic inflammation inherent in aging (inflammaging). […] Progerin seems to compromise the proper localization of SIRT1 and SIRT6 known to play important roles in mammalian aging. […] Progerin-induced changes in ING1 distribution could globally affect DNA methylation. […] Progerin may be involved both in tumor protection and metabolic adaptations. […] The accelerated aging phenotype in HGPS is a consequence of progerin-impaired nuclear envelope structure that might lead to nuclear leakiness and disruption of nucleocytoplasmic compartmentalization.

• #25 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  The HutchinsonGilford progeria syndrome (HGPS) is a premature aging disease caused by mutations of the LMNA gene leading to increased production of a partially processed form of the nuclear fibrillar protein lamin A progerin. Progerin acts as a dominant factor that leads to multiple morphological anomalies of cell nuclei and disturbances in heterochromatin organization, mitosis, DNA replication and repair, and gene transcription. […] Progerin-dependent mechanisms act in natural aging. Excessive activity of the same mechanisms may well be the cause of premature aging in HGPS. […] The chronological aging in normal individuals and the premature aging in HGPS patients are mediated by similar changes in the activity of signaling pathways, including downregulation of DNA repair and chromatin organization, and upregulation of ERK, mTOR, GH-IGF1, MAPK, TGF, and mitochondrial dysfunction.

• #26 Hutchinson-Gilford Progeria Syndrome: An Overview of the Molecular Mechanism, Pathophysiology and Therapeutic Approach

  https://scholar.xjtlu.edu.cn/en/publications/hutchinson-gilford-progeria-syndrome-an-overview-of-the-molecular

  Lamin A/C encoded by the LMNA gene is an essential component for maintaining the nuclear structure. […] HGPS is an immensely uncommon, deadly, metameric ill-timed laminopathies caused by the abnormal splicing of the LMNA gene and production of an aberrant protein known as progerin. […] Here, we also presented the currently available data on the molecular mechanism, pathophysiology, available treatment, and future approaches to this deadly disease. […] Due to the production of progerin, an abnormal protein leads to an abnormality in nuclear structure, defects in DNA repair, shortening of telomere, and impairment in gene regulation which ultimately results in aging in the early stage of life. […] Now some treatment options are available for this disease, but a proper understanding of the molecular mechanism of this disease will help to develop a more appropriate treatment which makes it an emerging area of research.

• #27 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  Progerin seems to be produced and accumulated in small quantities in wild-type fibroblasts. […] Progerin-dependent mechanisms play a role in natural aging, and the excessive activity of these mechanisms causes premature aging in HGPS. […] Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. […] Progerin acts as a dominant factor that directly and quickly disturbs the nuclear morphology. […] The permanent farnesylation of progerin has been proposed to be one of the leading causes of HGPS phenotype. […] Progerin could impact the VDR gene epigenetic status, leading to its repression, thus contributing to HGPS phenotype.

• #28

  https://link.springer.com/article/10.1007/s00418-016-1411-1

  HGPS-causing mutations have been shown to affect many fundamental cellular processes, but how these contribute to the described pathologies is not completely understood. […] Progerin expression may also affect genome stability by negatively affecting DNA damage repair pathways. […] HGPS cells were found to undergo accelerated telomere shortening when grown in culture, and ectopic expression of progerin in wild-type fibroblasts leads to accumulation of DNA damage at telomeres, both resulting in proliferation arrest and senescence. […] Progerin expression causes misregulation of various signaling pathways as shown in numerous examples; the molecular mechanisms, however, remain mostly obscure. […] Overall, a deregulation of ECM production and remodeling could account for both an impaired proliferation and differentiation of osteoblasts and chondrocytes during cartilage development, as well as an excessive ECM deposition in the vascular system causing increased arterial stiffness in HGPS.

• #29

  https://omim.org/entry/176670

  Using various mechanical measurements, including photobleaching assays, biophysical analysis under hypo- and hyperosmotic conditions, and micropipette aspiration, Dahl et al. (2006) demonstrated that the lamina in HGPS cells has a reduced ability to rearrange after mechanical stress compared to wildtype cells. In response to dynamic changes in the cell, mutant LMNA associated more tightly with the nuclear lamina than wildtype LMNA. Polarization microscopy studies showed that the lamins in HGPS nuclei were birefringent, forming orientationally ordered microdomains with reduced deformability. Dahl et al. (2006) suggested that the altered mechanical properties of HGPS cells may lead to misexpression of mechanosensitive genes. […] Hennekam (2006) noted that the HGPS-like disorder, mandibuloacrodysplasia with type B lipodystrophy (MADB; 608612), and restrictive dermopathy (275210) are both caused by mutation in the ZMPSTE24 gene (606480), resulting in abnormal posttranslational processing of lamin A. The author suggested that patients with atypical progeria may have ZMPSTE24 mutation.

• #30

  https://omim.org/entry/176670

  Using various mechanical measurements, including photobleaching assays, biophysical analysis under hypo- and hyperosmotic conditions, and micropipette aspiration, Dahl et al. (2006) demonstrated that the lamina in HGPS cells has a reduced ability to rearrange after mechanical stress compared to wildtype cells. In response to dynamic changes in the cell, mutant LMNA associated more tightly with the nuclear lamina than wildtype LMNA. Polarization microscopy studies showed that the lamins in HGPS nuclei were birefringent, forming orientationally ordered microdomains with reduced deformability. Dahl et al. (2006) suggested that the altered mechanical properties of HGPS cells may lead to misexpression of mechanosensitive genes. […] Hennekam (2006) noted that the HGPS-like disorder, mandibuloacrodysplasia with type B lipodystrophy (MADB; 608612), and restrictive dermopathy (275210) are both caused by mutation in the ZMPSTE24 gene (606480), resulting in abnormal posttranslational processing of lamin A. The author suggested that patients with atypical progeria may have ZMPSTE24 mutation.

• #31

  https://omim.org/entry/176670

  Using various mechanical measurements, including photobleaching assays, biophysical analysis under hypo- and hyperosmotic conditions, and micropipette aspiration, Dahl et al. (2006) demonstrated that the lamina in HGPS cells has a reduced ability to rearrange after mechanical stress compared to wildtype cells. In response to dynamic changes in the cell, mutant LMNA associated more tightly with the nuclear lamina than wildtype LMNA. Polarization microscopy studies showed that the lamins in HGPS nuclei were birefringent, forming orientationally ordered microdomains with reduced deformability. Dahl et al. (2006) suggested that the altered mechanical properties of HGPS cells may lead to misexpression of mechanosensitive genes. […] Hennekam (2006) noted that the HGPS-like disorder, mandibuloacrodysplasia with type B lipodystrophy (MADB; 608612), and restrictive dermopathy (275210) are both caused by mutation in the ZMPSTE24 gene (606480), resulting in abnormal posttranslational processing of lamin A. The author suggested that patients with atypical progeria may have ZMPSTE24 mutation.

• #32 Mechanisms of vascular aging: What can we learn from Hutchinson-Gilford progeria syndrome? | Clínica e Investigación en Arteriosclerosis (English Edition)

  https://www.elsevier.es/en-revista-clinica-e-investigacion-arteriosclerosis-english-415-articulo-mechanisms-vascular-aging-what-can-S2529912318000311

  Progerin-induced alterations to mechanotransduction could be explained by changes in the expression of proteins that control cytoskeletal organisation, mechanotransduction and production of the extracellular matrix. […] Expression of prelamin A in VSMCs promotes vascular calcification by activating the ataxia-telangiectasia-mutated/ataxia-telangiectasia and Rad3-related signalling pathway, which is associated with DNA damage. […] Endothelial dysfunction plays a fundamental role in all phases of atherosclerosis, the disease that compromises the lives of HGPS patients.

• #33 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  The HutchinsonGilford progeria syndrome (HGPS) is a premature aging disease caused by mutations of the LMNA gene leading to increased production of a partially processed form of the nuclear fibrillar protein lamin A progerin. Progerin acts as a dominant factor that leads to multiple morphological anomalies of cell nuclei and disturbances in heterochromatin organization, mitosis, DNA replication and repair, and gene transcription. […] Progerin-dependent mechanisms act in natural aging. Excessive activity of the same mechanisms may well be the cause of premature aging in HGPS. […] The chronological aging in normal individuals and the premature aging in HGPS patients are mediated by similar changes in the activity of signaling pathways, including downregulation of DNA repair and chromatin organization, and upregulation of ERK, mTOR, GH-IGF1, MAPK, TGF, and mitochondrial dysfunction.

• #34

  https://www.cnic.es/en/noticias/jci-new-study-reveals-key-mechanism-driving-atherosclerosis-hutchinson-gilford-progeria

  A team of scientists from the CNIC and the CSIC has identified a key mechanism in the development of atherosclerosis in patients with the rare genetic disease Hutchinson-Gilford progeria syndrome. […] In the study, the researchers identify the activation of the YAP/TAZ pathway in endothelial cells as a major contributor to the development of atherosclerosis in HGPS. […] HGPS is caused by a mutation in the LMNA gene that leads to the synthesis of a toxic protein called progerin. This mutant protein disrupts normal cell function and accelerates cell aging. […] The results show that endothelial cells in HGPS undergo significant changes in gene expression related to inflammation, immune-cell recruitment, and the stiffening of the surrounding extracellular matrix. One of the most striking findings was the activation of the YAP/TAZ signaling pathway, a critical regulator of how cells respond to mechanical forces such as blood flow and the stiffness of their environment.

• #35 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241007/Researchers-identify-key-mechanism-behind-atherosclerosis-in-Hutchinson-Gilford-progeria-syndrome.aspx

  In the study, the researchers identify the activation of the YAP/TAZ pathway in endothelial cells as a major contributor to the development of atherosclerosis in HGPS. […] The results show that endothelial cells in HGPS undergo significant changes in gene expression related to inflammation, immune-cell recruitment, and the stiffening of the surrounding extracellular matrix. One of the most striking findings was the activation of the YAP/TAZ signaling pathway, a critical regulator of how cells respond to mechanical forces such as blood flow and the stiffness of their environment. In HGPS mice, this pathway was found to be abnormally active in endothelial cells from the aorta, the main artery carrying blood from the heart to the rest of the body. […] Our findings suggest that the stiffening of the arterial wall and the changes in blood flow patterns in HGPS trigger the activation of the YAP/TAZ pathway in endothelial cells. This in turn promotes inflammation and the accumulation of immune cells in the arteries, which accelerates the development of atherosclerosis.

• #36

  https://www.cnic.es/en/noticias/jci-new-study-reveals-key-mechanism-driving-atherosclerosis-hutchinson-gilford-progeria

  A team of scientists from the CNIC and the CSIC has identified a key mechanism in the development of atherosclerosis in patients with the rare genetic disease Hutchinson-Gilford progeria syndrome. […] In the study, the researchers identify the activation of the YAP/TAZ pathway in endothelial cells as a major contributor to the development of atherosclerosis in HGPS. […] HGPS is caused by a mutation in the LMNA gene that leads to the synthesis of a toxic protein called progerin. This mutant protein disrupts normal cell function and accelerates cell aging. […] The results show that endothelial cells in HGPS undergo significant changes in gene expression related to inflammation, immune-cell recruitment, and the stiffening of the surrounding extracellular matrix. One of the most striking findings was the activation of the YAP/TAZ signaling pathway, a critical regulator of how cells respond to mechanical forces such as blood flow and the stiffness of their environment.

• #37 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241007/Researchers-identify-key-mechanism-behind-atherosclerosis-in-Hutchinson-Gilford-progeria-syndrome.aspx

  In the study, the researchers identify the activation of the YAP/TAZ pathway in endothelial cells as a major contributor to the development of atherosclerosis in HGPS. […] The results show that endothelial cells in HGPS undergo significant changes in gene expression related to inflammation, immune-cell recruitment, and the stiffening of the surrounding extracellular matrix. One of the most striking findings was the activation of the YAP/TAZ signaling pathway, a critical regulator of how cells respond to mechanical forces such as blood flow and the stiffness of their environment. In HGPS mice, this pathway was found to be abnormally active in endothelial cells from the aorta, the main artery carrying blood from the heart to the rest of the body. […] Our findings suggest that the stiffening of the arterial wall and the changes in blood flow patterns in HGPS trigger the activation of the YAP/TAZ pathway in endothelial cells. This in turn promotes inflammation and the accumulation of immune cells in the arteries, which accelerates the development of atherosclerosis.

• #38 Mechanism of aging recovery for progeria patients revealed

  https://medicalxpress.com/news/2017-04-mechanism-aging-recovery-progeria-patients.html

  DGIST’s research team has identified a mechanism that can recover the aging of patients with Hutchinson-Gilford Progeria Syndrome (HGPS). […] This study needs to be highlighted as the research team has identified the molecular causal relationship between ROCK protein activation and mitochondrial dysfunction in the progression of cell senescence for the first time in the world. […] The research team found that 'Y-27632′ drug inhibits the phosphorylation level of ROCK and increases the oxidative phosphorylation efficiency of mitochondria. The study also confirms that the drug recovers mitochondrial function and induces the recovery of aging cells by reducing nuclear membrane degeneration and genetic damage that are characteristics of HGPS patient cells. […] The Chair Professor Park SangChul stated „This study is significant as we have newly discovered the means to control aging. We have also identified the mechanism to recover the function of aging cell through inhibition and recovery of mitochondrial dysfunction due to aging.”

• #39 Mechanism of aging recovery for progeria patients revealed

  https://medicalxpress.com/news/2017-04-mechanism-aging-recovery-progeria-patients.html

  DGIST’s research team has identified a mechanism that can recover the aging of patients with Hutchinson-Gilford Progeria Syndrome (HGPS). […] This study needs to be highlighted as the research team has identified the molecular causal relationship between ROCK protein activation and mitochondrial dysfunction in the progression of cell senescence for the first time in the world. […] The research team found that 'Y-27632′ drug inhibits the phosphorylation level of ROCK and increases the oxidative phosphorylation efficiency of mitochondria. The study also confirms that the drug recovers mitochondrial function and induces the recovery of aging cells by reducing nuclear membrane degeneration and genetic damage that are characteristics of HGPS patient cells. […] The Chair Professor Park SangChul stated „This study is significant as we have newly discovered the means to control aging. We have also identified the mechanism to recover the function of aging cell through inhibition and recovery of mitochondrial dysfunction due to aging.”

• #40 Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification | eLife

  https://elifesciences.org/articles/81290

  The expression of a mutant Lamin A, progerin, in Hutchinson-Gilford Progeria Syndrome leads to alterations in genome architecture, nuclear morphology, epigenetic states, and altered phenotypes in all cells of the mesenchymal lineage. […] We find that Progeria fibroblasts carry abnormal transcriptional signatures, centering around several functional hubs: DNA maintenance and epigenetics, bone development and homeostasis, blood vessel maturation and development, fat deposition and lipid management, and processes related to muscle growth. […] Our results show that transcription of genes involved in negative regulation of chondrocyte commitment is compromised in fibroblasts from patients that are at the age of onset of postnatal endochondral ossification. […] Our results support the hypothesis that defects in the initial steps of chondrogenesis commitment are a potential mechanism for mesenchymal stem cell depletion that later results in abnormal adipogenesis, diminished microvasculature homeostasis, and poor wound repair observed in HGPS patients.

• #41 Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification | eLife

  https://elifesciences.org/articles/81290

  The expression of a mutant Lamin A, progerin, in Hutchinson-Gilford Progeria Syndrome leads to alterations in genome architecture, nuclear morphology, epigenetic states, and altered phenotypes in all cells of the mesenchymal lineage. […] We find that Progeria fibroblasts carry abnormal transcriptional signatures, centering around several functional hubs: DNA maintenance and epigenetics, bone development and homeostasis, blood vessel maturation and development, fat deposition and lipid management, and processes related to muscle growth. […] Our results show that transcription of genes involved in negative regulation of chondrocyte commitment is compromised in fibroblasts from patients that are at the age of onset of postnatal endochondral ossification. […] Our results support the hypothesis that defects in the initial steps of chondrogenesis commitment are a potential mechanism for mesenchymal stem cell depletion that later results in abnormal adipogenesis, diminished microvasculature homeostasis, and poor wound repair observed in HGPS patients.

• #42 Transcriptional profiling of Hutchinson-Gilford Progeria syndrome fibroblasts reveals deficits in mesenchymal stem cell commitment to differentiation related to early events in endochondral ossification | eLife

  https://elifesciences.org/articles/81290

  The expression of a mutant Lamin A, progerin, in Hutchinson-Gilford Progeria Syndrome leads to alterations in genome architecture, nuclear morphology, epigenetic states, and altered phenotypes in all cells of the mesenchymal lineage. […] We find that Progeria fibroblasts carry abnormal transcriptional signatures, centering around several functional hubs: DNA maintenance and epigenetics, bone development and homeostasis, blood vessel maturation and development, fat deposition and lipid management, and processes related to muscle growth. […] Our results show that transcription of genes involved in negative regulation of chondrocyte commitment is compromised in fibroblasts from patients that are at the age of onset of postnatal endochondral ossification. […] Our results support the hypothesis that defects in the initial steps of chondrogenesis commitment are a potential mechanism for mesenchymal stem cell depletion that later results in abnormal adipogenesis, diminished microvasculature homeostasis, and poor wound repair observed in HGPS patients.

• #43 Mechanisms of vascular aging: What can we learn from Hutchinson-Gilford progeria syndrome? | Clínica e Investigación en Arteriosclerosis (English Edition)

  https://www.elsevier.es/en-revista-clinica-e-investigacion-arteriosclerosis-english-415-articulo-mechanisms-vascular-aging-what-can-S2529912318000311

  Ageing is the main risk factor for cardiovascular disease (CVD). The increased prevalence of CVD is partly due to the global increase in life expectancy. […] Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by the synthesis of progerin, which is noted for accelerated ageing and CVD. This mutant form of prelamin A induces generalised atherosclerosis, vascular calcification, and cardiac electrophysiological abnormalities, leading to premature ageing and death, mainly due to myocardial infarction and stroke. […] Research into HGPS could therefore shed light on novel mechanisms involved in the physiological ageing of the cardiovascular system. […] Patients with HGPS exhibit premature ageing associated with accelerated atherosclerosis and vascular calcification, together with the development of cardiac electrical conduction defects.

• #44 Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

  https://www.mdpi.com/2073-4409/10/5/1157

  The data accumulated over several decades indicates that the HGPS cardiovascular phenotype is defined by generalized atherosclerosis with a wide spectrum of early- to late-stage atherosclerotic plaques, prominent VSMC loss, vascular stiffening, calcification and fibrosis, cardiac repolarization abnormalities, LV diastolic dysfunction, and cardiac valve disease, all of which probably contribute to the death of HGPS patients from myocardial infarction, stroke, or heart failure. […] The discovery of the genetic mutation causing classical HGPS in 2003 triggered the generation of a number of HGPS experimental models that play a pivotal role in the investigation of progerin-induced alterations and the testing of new therapeutic approaches. […] Progerin expression has been detected in VSMCs and ECs in HGPS patients.

• #45 Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

  https://www.mdpi.com/2073-4409/10/5/1157

  The data accumulated over several decades indicates that the HGPS cardiovascular phenotype is defined by generalized atherosclerosis with a wide spectrum of early- to late-stage atherosclerotic plaques, prominent VSMC loss, vascular stiffening, calcification and fibrosis, cardiac repolarization abnormalities, LV diastolic dysfunction, and cardiac valve disease, all of which probably contribute to the death of HGPS patients from myocardial infarction, stroke, or heart failure. […] The discovery of the genetic mutation causing classical HGPS in 2003 triggered the generation of a number of HGPS experimental models that play a pivotal role in the investigation of progerin-induced alterations and the testing of new therapeutic approaches. […] Progerin expression has been detected in VSMCs and ECs in HGPS patients.

• #46 Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

  https://www.mdpi.com/2073-4409/10/5/1157

  Progerin expression in cultured mouse VSMCs increases cell death in response to mechanical stress in a LINC complex-dependent manner. […] Progerin expression has been detected in VSMCs and ECs in HGPS patients. […] Progerin expression in cultured mouse VSMCs increases cell death in response to mechanical stress in a LINC complex-dependent manner. […] The pulsatile flow of blood in the arteries subjects the arterial wall to continuous mechanical stress. For reasons that remain elusive, progerin-expressing VSMCs appear to be particularly sensitive to this constant cyclic insult, which induces ER stress, dedifferentiation, calcification (and possibly acquisition of an osteogenic phenotype), DNA damage, and eventually VSMC death, probably due to progerin-mediated altered nucleocytoskeletal connections and defective intracellular force transmission.

• #47 Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

  https://www.mdpi.com/2073-4409/10/5/1157

  Progerin expression in cultured mouse VSMCs increases cell death in response to mechanical stress in a LINC complex-dependent manner. […] Progerin expression has been detected in VSMCs and ECs in HGPS patients. […] Progerin expression in cultured mouse VSMCs increases cell death in response to mechanical stress in a LINC complex-dependent manner. […] The pulsatile flow of blood in the arteries subjects the arterial wall to continuous mechanical stress. For reasons that remain elusive, progerin-expressing VSMCs appear to be particularly sensitive to this constant cyclic insult, which induces ER stress, dedifferentiation, calcification (and possibly acquisition of an osteogenic phenotype), DNA damage, and eventually VSMC death, probably due to progerin-mediated altered nucleocytoskeletal connections and defective intracellular force transmission.

• #48

  https://www.cnic.es/en/noticias/circulation-new-mechanism-early-onset-atherosclerosis-premature-aging-syndrome

  The new study, published in the journal Circulation, opens a new avenue of research into treatments for the atherosclerosis associated with progeria. […] Scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have identified the process of endothelial-to-mesenchymal transition (EndMT) as a novel mechanism in premature atherosclerosis in progeria. […] This earlier work also demonstrated that one of the main causes of the accelerated atherosclerosis associated with this syndrome is the death of smooth muscle cells in the artery wall. […] Co-first author Dr. Rosa Nevado explained that in progeria, the loss of smooth muscle cells induces a series of pathological alterations in the neighboring endothelial cells. […] But Dr. Andrs emphasized that the most startling change in endothelial cells from progeroid mice is the hyperactivation of phenotypic modulation via EndMT. […] The authors also conducted an in-depth analysis of the molecular mechanisms of EndMT in progeria. […] Dr. Hamczyk concluded, this study describes new cellular and molecular mechanisms involved in atherosclerosis and proposes a new therapeutic target for this disease.

• #49

  https://www.cnic.es/en/noticias/circulation-new-mechanism-early-onset-atherosclerosis-premature-aging-syndrome

  The new study, published in the journal Circulation, opens a new avenue of research into treatments for the atherosclerosis associated with progeria. […] Scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have identified the process of endothelial-to-mesenchymal transition (EndMT) as a novel mechanism in premature atherosclerosis in progeria. […] This earlier work also demonstrated that one of the main causes of the accelerated atherosclerosis associated with this syndrome is the death of smooth muscle cells in the artery wall. […] Co-first author Dr. Rosa Nevado explained that in progeria, the loss of smooth muscle cells induces a series of pathological alterations in the neighboring endothelial cells. […] But Dr. Andrs emphasized that the most startling change in endothelial cells from progeroid mice is the hyperactivation of phenotypic modulation via EndMT. […] The authors also conducted an in-depth analysis of the molecular mechanisms of EndMT in progeria. […] Dr. Hamczyk concluded, this study describes new cellular and molecular mechanisms involved in atherosclerosis and proposes a new therapeutic target for this disease.

• #50 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  Progerin seems to be produced and accumulated in small quantities in wild-type fibroblasts. […] Progerin-dependent mechanisms play a role in natural aging, and the excessive activity of these mechanisms causes premature aging in HGPS. […] Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. […] Progerin acts as a dominant factor that directly and quickly disturbs the nuclear morphology. […] The permanent farnesylation of progerin has been proposed to be one of the leading causes of HGPS phenotype. […] Progerin could impact the VDR gene epigenetic status, leading to its repression, thus contributing to HGPS phenotype.

• #51 Are There Common Mechanisms Between the Hutchinson–Gilford Progeria Syndrome and Natural Aging?

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6529819/

  Progerin seems to be produced and accumulated in small quantities in wild-type fibroblasts. […] Progerin-dependent mechanisms play a role in natural aging, and the excessive activity of these mechanisms causes premature aging in HGPS. […] Progerin expression in normal human fibroblasts accelerates the loss of telomeres. Changes in lamina organization may directly affect telomere attrition resulting in accelerated replicative senescence and progeroid phenotypes. […] Progerin acts as a dominant factor that directly and quickly disturbs the nuclear morphology. […] The permanent farnesylation of progerin has been proposed to be one of the leading causes of HGPS phenotype. […] Progerin could impact the VDR gene epigenetic status, leading to its repression, thus contributing to HGPS phenotype.

• #52

  https://openarchive.ki.se/articles/thesis/The_genetic_mechanism_that_links_Hutchinson-Gilford_progeria_syndrome_to_physiological_aging/26894845

  Aging is a complex process that is not completely understood. The study of segmental progeroid syndromes such as Hutchinson-Gilford progeria syndrome (HGPS) has allowed us to connect the common genetic mechanisms that occur in normal physiological aging, with the cellular alterations presented by this severe premature aging syndrome. Since the identification of mutations in the lamin A/C coding LMNA gene that cause HGPS and other laminopathies, there has been an increasing interest in the potential role of lamins in the normal aging process. Progerin, a mutant form of lamin A, has attracted particular great attention. LMNA mutations in HGPS activate a cryptic splice site, leading to an aberrant splicing of lamin A, which results in a lamin A150 transcript and progerin. Recent research data, including the results presented in this thesis, provide support for the possibility of a shared mechanism between natural physiological aging and pathological aging occurring in HGPS.

• #53

  https://openarchive.ki.se/articles/thesis/The_genetic_mechanism_that_links_Hutchinson-Gilford_progeria_syndrome_to_physiological_aging/26894845

  Aging is a complex process that is not completely understood. The study of segmental progeroid syndromes such as Hutchinson-Gilford progeria syndrome (HGPS) has allowed us to connect the common genetic mechanisms that occur in normal physiological aging, with the cellular alterations presented by this severe premature aging syndrome. Since the identification of mutations in the lamin A/C coding LMNA gene that cause HGPS and other laminopathies, there has been an increasing interest in the potential role of lamins in the normal aging process. Progerin, a mutant form of lamin A, has attracted particular great attention. LMNA mutations in HGPS activate a cryptic splice site, leading to an aberrant splicing of lamin A, which results in a lamin A150 transcript and progerin. Recent research data, including the results presented in this thesis, provide support for the possibility of a shared mechanism between natural physiological aging and pathological aging occurring in HGPS.

• #54

  https://openarchive.ki.se/articles/thesis/The_genetic_mechanism_that_links_Hutchinson-Gilford_progeria_syndrome_to_physiological_aging/26894845

  The overall aim of this thesis was to gain an increased understanding of potential common genetic mechanisms behind Hutchinson-Gilford progeria syndrome and normal physiological aging. […] We show that aging affects splicing via a considerable number of genes displaying significant differential and increased splicing with age. The most significantly enriched biological functions with alternative spliced genes during normal aging included RNA processing and the spliceosome pathway. Additionally, progeria cells had primarily differential splicing of extra cellular matrix genes, and explorative network enrichment analysis identified the NF-B complex as a potential common network node for HGPS and normal tissue aging.

• #55 Molecular ageing in progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model | Immunity & Ageing | Full Text

  https://immunityageing.biomedcentral.com/articles/10.1186/1742-4933-6-4

  Affected nuclear mechanisms and secondary alterations in gene expression may cause damage to the striated muscle of individuals with certain mutations in lamin A/C. Different mutations in lamins A and C may cause various tissue-specific pathological phenotypes. […] There is no known cure for progeria. Nonetheless, there are treatments in order to improve the clinical conditions. […] Another therapeutic approach involves the use of farnesyltransferase inhibitors which have been shown to reverse abnormalities in nuclear morphology in cells expressing progerin.

• #56 Hutchinson-Gilford Progeria Syndrome: Pathophysiology and Possible Treatments

  https://touroscholar.touro.edu/sjlcas/vol7/iss2/9/

  Named after the two scientists who independently described the condition, Hutchinson-Gilford Progeria Syndrome (HGPS) occurs due to a mutation in the LMNA gene that codes for Lamin A, a filament protein that acts to form the nuclear lamina in the cell nucleus. This mutation is a single C-to-T substitution at nucleotide 1824 of the LMNA gene. As a result of this mutation, an abnormal protein named 'progerin’ is synthesized instead of Lamin A, causing the nuclear membrane to be malformed. […] Since protein farnesylation is needed to target progerin to the nuclear rim, farnesyltransferase inhibitor has been proposed as a form of treatment that could reduce the occurrence of misshapen nuclei and alleviate HGPS symptoms.

• #57 Studying the Molecular Mechanism of Post-Translational Modification of Lamin A in Hutchinson-Gilford Progeria Syndrome

  https://www.lakeforest.edu/news/studying-the-molecular-mechanism-of-post-translational-modification-of-lamin-a-in-hutchinson-gilford-progeria-syndrome

  Hutchinson-Gilford Progeria Syndrome (HGPS) is a genetic condition that presents itself as premature aging. It is caused by a point mutation in exon eleven of the LMNA gene. This gene is responsible for producing lamin A and lamin C proteins. The point mutation is a silent mutation that causes the splicing pattern of LMNA to be altered resulting in a mutant protein called progerin to form. The build-up of this protein causes HGPS. […] FTIs help alleviate the symptoms of afflicted children and hopefully can be utilized in the future as a cure. […] The mutation is classified as a de novo mutation where the mutation is received without either parent having the point mutation. However, it is unclear when this mutation occurs. HGPS is an autosomal dominant condition, thus only one mutant LMNA allele is necessary for the condition. The mutation is a silent mutation in exon eleven of the LMNA gene on chromosome one. A silent mutation is a point mutation in the genome, but the amino acid sequence is not altered. Therefore, change of a cytosine to a thymine in exon eleven results in glycine remaining as the amino acid in the primary structure of lamin A. However, the silent mutation alters the splicing pattern of the LMNA gene where an additional gene product is produced known as a progerin. The activation of this splice variant results in the deletion of fifty amino acids from the C-terminal end of the protein. This causes an abnormal immature lamin A protein to be produced since the protein cannot undergo post-translation modifications due to the fifty amino acid deletion. Therefore, the silent mutation prevents the proper synthesis of lamin A since the mature protein is unable to be produced.

• #58 Studying the Molecular Mechanism of Post-Translational Modification of Lamin A in Hutchinson-Gilford Progeria Syndrome

  https://www.lakeforest.edu/news/studying-the-molecular-mechanism-of-post-translational-modification-of-lamin-a-in-hutchinson-gilford-progeria-syndrome

  The results received from FTIs were so promising that human trials have been conducted. Preliminary FTI trials have been tested in humans to determine if it can extend the lifespan of afflicted individuals. The drug Lonafarib was utilized in the trial, which reversibly binds to the active site of a farnesyltransferase where the CSIM motif typically binds so the cysteine residue can be farnesylated. Thus, competitively inhibiting this enzyme should prevent pre-lamin A from being farnesylated and prevent progerin from accumulating on the nuclear envelope. The results of the study were promising since every patient showed an improvement in at least one of the symptoms caused by HGPS. Lonafarib improved cardiovascular disease in patients as demonstrated by improved vascular elasticity. This is crucial because cardiovascular disease is typically the cause of death of HGPS patients. Although Lonafarib is not a cure, it is a valuable first step towards treating individuals with HGPS by helping to alleviate symptoms and improving quality of life.

• #59 FDA Approves First Treatment for Hutchinson-Gilford Progeria Syndrome and Some Progeroid Laminopathies | FDA

  https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-hutchinson-gilford-progeria-syndrome-and-some-progeroid-laminopathies

  Hutchinson-Gilford progeria syndrome and progeroid laminopathies are rare genetic diseases that cause premature aging and death and have a debilitating effect on peoples lives. […] Patients with Hutchinson-Gilford progeria syndrome and progeroid laminopathies experience accelerated cardiovascular disease from the buildup of defective progerin or progerin-like protein in cells. […] Zokinvy, a farnesyltransferase inhibitor, is an oral medication that helps prevent the buildup of defective progerin or progerin-like protein. […] Zokinvys approval for the treatment of certain processing-deficient progeroid laminopathies that are very rare took into account similarities in the underlying genetic mechanism of disease and other available data.

• #60 About Zokinvy for HCPs | Sentynl Therapeutics, Inc.

  https://www.zokinvy.com/hcp/about-zokinvy

  Zokinvy is a farnesyltransferase inhibitor that prevents the accumulation of cellular progerin and progerin-like proteins. For the very first time, you can help enable patients to live longer lives. […] By inhibiting farnesylation, Zokinvy targets a key step in the pathophysiology of Progeria and PDPL. […] Zokinvy inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane. […] Zokinvy prevents the accumulation of progerin and progerin-like proteins, resulting in restoration of nuclear morphology. […] The efficacy of ZOKINVY was determined based on results from the Observational Cohort Survival Study, which retrospectively compared survival data from two phase 2 studies in patients with Progeria with those from an untreated cohort.

• #61 About Zokinvy for HCPs | Sentynl Therapeutics, Inc.

  https://www.zokinvy.com/hcp/about-zokinvy

  At last follow-up, treatment with Zokinvy resulted in increased mean survival of 2.5 years and a 60% reduction in risk of mortality. […] At a 3-year follow-up, there was a 70% reduction in risk of mortality. At last follow-up (11 years), the reduction was 60%. […] Zokinvy improves cardiovascular outcomes in patients with Progeria or PDPL. […] Analysis of clinical data from both studies indicates that after the first 4 months of treatment, adverse reactions decreased by 70%-80%. […] Adverse reactions, including gastrointestinal issues, can be successfully managed with supportive care and generally decrease over time.

• #62

  https://www.cnic.es/en/noticias/circulation-new-mechanism-early-onset-atherosclerosis-premature-aging-syndrome

  The new study, published in the journal Circulation, opens a new avenue of research into treatments for the atherosclerosis associated with progeria. […] Scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) have identified the process of endothelial-to-mesenchymal transition (EndMT) as a novel mechanism in premature atherosclerosis in progeria. […] This earlier work also demonstrated that one of the main causes of the accelerated atherosclerosis associated with this syndrome is the death of smooth muscle cells in the artery wall. […] Co-first author Dr. Rosa Nevado explained that in progeria, the loss of smooth muscle cells induces a series of pathological alterations in the neighboring endothelial cells. […] But Dr. Andrs emphasized that the most startling change in endothelial cells from progeroid mice is the hyperactivation of phenotypic modulation via EndMT. […] The authors also conducted an in-depth analysis of the molecular mechanisms of EndMT in progeria. […] Dr. Hamczyk concluded, this study describes new cellular and molecular mechanisms involved in atherosclerosis and proposes a new therapeutic target for this disease.

• #63

  https://www.cnic.es/en/noticias/jci-new-study-reveals-key-mechanism-driving-atherosclerosis-hutchinson-gilford-progeria

  Our findings suggest that the stiffening of the arterial wall and the changes in blood flow patterns in HGPS trigger the activation of the YAP/TAZ pathway in endothelial cells. This in turn promotes inflammation and the accumulation of immune cells in the arteries, which accelerates the development of atherosclerosis. […] By targeting the YAP/TAZ pathway, we were able to significantly reduce the progression of atherosclerosis in our HGPS mouse model. […] Our study represents an important advance in understanding the mechanisms behind vascular aging in HGPS. […] The insights we’ve gained from studying HGPS can help us gain a better understanding of the aging process in general and of the factors that contribute to cardiovascular disease in older individuals.

• #64 A key mechanism in the development of cardiovascular disease in Hutchinson-Gilford progeria syndrome uncovered | Centro de Investigaciones Biológicas Margarita Salas – CIB Margarita Salas

  https://www.cib.csic.es/news/research/key-mechanism-development-cardiovascular-disease-hutchinson-gilford-progeria-syndrome

  The results showed that treatment of HGPS mice with verteporfin significantly decreased the development of atherosclerosis, additionally reducing endothelial cell activation and immune cell accumulation in the aorta, two key factors in atherosclerosis. […] Our study represents an important step in understanding the mechanisms behind vascular ageing in HGPS, notes Dr Barettino. However, translating these findings into a safe and effective treatment for patients will require further research. […] The knowledge we have gained from studying HGPS may help us to better understand the ageing process in general and the factors that contribute to cardiovascular disease in older people, adds Dr Andrs.

• #65 Unique progerin C-terminal peptide ameliorates Hutchinson–Gilford progeria syndrome phenotype by rescuing BUBR1 | Nature Aging

  https://www.nature.com/articles/s43587-023-00361-w

  An accumulating body of evidence indicates an association between mitotic defects and the aging process in Hutchinson-Gilford progeria syndrome (HGPS), which is a premature aging disease caused by progerin accumulation. […] The remaining BUBR1 was anchored to the nuclear membrane by binding with the C terminus of progerin, thus further limiting the function of BUBR1. […] Our findings reveal an essential role for the progerin-PTBP1-BUBR1 axis in HGPS. […] However, the mechanism of how progerin causes mitotic defects in HGPS cells is unclear. […] BUBR1 is encoded by BUB1B and is a component of the SAC that has emerged as a key regulator of aging and longevity in mice. […] A decline in the BUBR1 level occurs with natural aging and induces progeroid features in mice and humans with mosaic variegated aneuploidy (MVA) syndrome.

• #66 Unique progerin C-terminal peptide ameliorates Hutchinson–Gilford progeria syndrome phenotype by rescuing BUBR1 | Nature Aging

  https://www.nature.com/articles/s43587-023-00361-w

  Together, these studies indicate that BUBR1 regulates mitosis and is an important contributor to normal aging. […] However, whether BUBR1 is involved in the development of HGPS has not been reported. […] We discovered that BUBR1 was downregulated in HGPS cells. […] BUBR1 significantly antagonized HGPS cellular senescence, including the increased level of CyclinA2, the reduced activity of SA–gal and the increased Ki67 positive staining in IMR90-progerin cells. […] BUBR1 antagonizes progerin-mediated HGPS cellular senescence, which means that BUBR1 plays an important role in HGPS. […] We have confirmed that progerin tethered BUBR1 to the nuclear membrane, which prompted us to examine whether BUBR1 could be released from the nuclear membrane by interfering with the interaction of progerin and BUBR1.

• #67 Unique progerin C-terminal peptide ameliorates Hutchinson–Gilford progeria syndrome phenotype by rescuing BUBR1 | Nature Aging

  https://www.nature.com/articles/s43587-023-00361-w

  Together, these studies indicate that BUBR1 regulates mitosis and is an important contributor to normal aging. […] However, whether BUBR1 is involved in the development of HGPS has not been reported. […] We discovered that BUBR1 was downregulated in HGPS cells. […] BUBR1 significantly antagonized HGPS cellular senescence, including the increased level of CyclinA2, the reduced activity of SA–gal and the increased Ki67 positive staining in IMR90-progerin cells. […] BUBR1 antagonizes progerin-mediated HGPS cellular senescence, which means that BUBR1 plays an important role in HGPS. […] We have confirmed that progerin tethered BUBR1 to the nuclear membrane, which prompted us to examine whether BUBR1 could be released from the nuclear membrane by interfering with the interaction of progerin and BUBR1.

• #68 Unique progerin C-terminal peptide ameliorates Hutchinson–Gilford progeria syndrome phenotype by rescuing BUBR1 | Nature Aging

  https://www.nature.com/articles/s43587-023-00361-w

  Our data demonstrate that UPCP interfered with the interaction of progerin and BUBR1 and upregulated BUBR1. […] UPCP alleviated HGPS cellular senescence through BUBR1. […] Collectively, UPCP treatment ameliorates progeroid features and extends lifespan in LmnaG609G/G609G mice. […] In this study, we unveiled a new regulatory mechanism of progerin-PTBP1-BUBR1 in HGPS cellular senescence. […] Our results demonstrated that PTBP1 stabilized BUBR1 mRNA by binding to the BUBR1 3-UTR. […] The interaction between UPCP and PTBP1 also released PTBP1 from progerin and promoted PTBP1 to stabilize BUBR1 mRNA, further upregulating the level of BUBR1.

• #69 Unique progerin C-terminal peptide ameliorates Hutchinson–Gilford progeria syndrome phenotype by rescuing BUBR1 | Nature Aging

  https://www.nature.com/articles/s43587-023-00361-w

  Our data demonstrate that UPCP interfered with the interaction of progerin and BUBR1 and upregulated BUBR1. […] UPCP alleviated HGPS cellular senescence through BUBR1. […] Collectively, UPCP treatment ameliorates progeroid features and extends lifespan in LmnaG609G/G609G mice. […] In this study, we unveiled a new regulatory mechanism of progerin-PTBP1-BUBR1 in HGPS cellular senescence. […] Our results demonstrated that PTBP1 stabilized BUBR1 mRNA by binding to the BUBR1 3-UTR. […] The interaction between UPCP and PTBP1 also released PTBP1 from progerin and promoted PTBP1 to stabilize BUBR1 mRNA, further upregulating the level of BUBR1.

• #70 All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype | Oncotarget

  https://www.oncotarget.com/article/4939/text/

  Currently, HGPS is an incurable disease. […] Different strategies were evaluated such as genetic approaches and pharmacological treatments focused on modulation of prelamin A maturation process, in order to reduce the final amount of farnesylated progerin. […] Moreover, promising results have been obtained in vitro by the use of rapamycin acting as an mTOR inhibitor which contributes to progerin degradation by activating autophagy. […] Interestingly, a retinoic acid responsive element (L-RARE) has been identified within the LMNA promoter, and several studies suggest that all-trans retinoic acid (ATRA) may either enhance or reduce, depending on the cellular model, the promoter activity of different genes. […] Aiming to reduce the intranuclear progerin accumulation, we investigated the effect of ATRA prolonged administration to HGPS skin fibroblasts.

• #71 The Dental and Oral Significance of Hutchinson-Gilford Progeria Syndrome

  https://www.scientificarchives.com/article/the-dental-and-oral-significance-of-hutchinsongilford-progeria-syndrome

  Lonafarnib, a Farnesyl Transferase inhibitor, has exhibited some limited success in improving the various conditions associated with HGPS. […] Another very interesting and promising recent research development is that the anti-diabetic drug metformin has been demonstrated to reduce progerin expression thus alleviating pathological phenotypes of HGPS.

• #72 All-trans retinoic acid and rapamycin normalize Hutchinson Gilford progeria fibroblast phenotype | Oncotarget

  https://www.oncotarget.com/article/4939/text/

  Hutchinson Gilford progeria syndrome is a fatal disorder characterized by accelerated aging, bone resorption and atherosclerosis, caused by a LMNA mutation which produces progerin, a mutant lamin A precursor. […] Progeria cells display progerin and prelamin A nuclear accumulation, altered histone methylation pattern, heterochromatin loss, increased DNA damage and cell cycle alterations. […] We demonstrate that all-trans retinoic acid acts synergistically with low-dosage rapamycin reducing progerin and prelamin A, via transcriptional downregulation associated with protein degradation, and increasing the lamin A to progerin ratio. […] The combined all-trans retinoic acid-rapamycin treatment is dramatically efficient, highly reproducible, represents a promising new approach in Hutchinson-Gilford Progeria therapy and deserves investigation in ageing-associated disorders.

• #73 The Dental and Oral Significance of Hutchinson-Gilford Progeria Syndrome

  https://www.scientificarchives.com/article/the-dental-and-oral-significance-of-hutchinsongilford-progeria-syndrome

  Lonafarnib, a Farnesyl Transferase inhibitor, has exhibited some limited success in improving the various conditions associated with HGPS. […] Another very interesting and promising recent research development is that the anti-diabetic drug metformin has been demonstrated to reduce progerin expression thus alleviating pathological phenotypes of HGPS.

• #74 AMPK: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome – Atlas of Science

  https://atlasofscience.org/ampk-common-mechanism-of-action-linking-hiv-1-latency-and-hutchinson-gilford-progeria-syndrome/

  AMPK: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome. […] Because AMPK, a master metabolic regulator activated by many naturally-occurring compounds (e.g. resveratrol and beberine) as well as metformin, is necessary for T cell activation and thus reactivation of latent HIV-1 but also controls the activity of the splicing factor ASF/SF2 via upregulation of p32, AMPK activation will lead to a potential correction of alternative splicing in the LMNA gene and reactivation of latent HIV-1. […] Moreover, rapamycin, a compound that has been shown to increase the lifespan of several animal model organisms, and sulforaphane, a naturally-occurring compound heavily concentrated in broccoli sprouts, have each been shown to increase clearance of the mutant progerin protein from the cell via autophagy (a system of disposing of damaged proteins in the cell).

• #75 AMPK: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome – Atlas of Science

  https://atlasofscience.org/ampk-common-mechanism-of-action-linking-hiv-1-latency-and-hutchinson-gilford-progeria-syndrome/

  AMPK: Common mechanism of action linking HIV-1 latency and Hutchinson-Gilford progeria syndrome. […] Because AMPK, a master metabolic regulator activated by many naturally-occurring compounds (e.g. resveratrol and beberine) as well as metformin, is necessary for T cell activation and thus reactivation of latent HIV-1 but also controls the activity of the splicing factor ASF/SF2 via upregulation of p32, AMPK activation will lead to a potential correction of alternative splicing in the LMNA gene and reactivation of latent HIV-1. […] Moreover, rapamycin, a compound that has been shown to increase the lifespan of several animal model organisms, and sulforaphane, a naturally-occurring compound heavily concentrated in broccoli sprouts, have each been shown to increase clearance of the mutant progerin protein from the cell via autophagy (a system of disposing of damaged proteins in the cell).

• #76 Mechanisms of angiogenic incompetence in Hutchinson-Gilford progeria via downregulation of endothelial NOS. | Broad Institute

  https://www.broadinstitute.org/publications/broad1348576

  Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder with features of accelerated aging. The majority of HGPS cases are caused by a de novo point mutation in the LMNA gene (c.1824CT; p.G608G) resulting in progerin, a toxic lamin A protein variant. […] Endothelial dysfunction is a known driver of cardiovascular pathogenesis; however, it is currently unknown how progerin antagonizes normal angiogenic function in HGPS. […] HGPS iPSC-ECs show reduced endothelial nitric oxide synthase (eNOS) expression and activity compared with normal controls and concomitant decreases in intracellular nitric oxide (NO) level, which result in deficits in capillary-like microvascular network formation. […] Finally, we used an adenine base editor (ABE7.10max-VRQR) to correct the pathogenic c.1824CT allele in HGPS iPSC-ECs. Remarkably, ABE7.10max-VRQR correction of the HGPS mutation significantly reduced progerin expression to a basal level, rescued nuclear blebbing, increased intracellular NO level, normalized the misregulated TIMPs, and restored angiogenic competence in HGPS iPSC-ECs. Together, these results provide molecular insights of endothelial dysfunction in HGPS and suggest that ABE could be a promising therapeutic approach for correcting HGPS-related cardiovascular phenotypes.

• #77 Defining the progeria phenome | Aging

  https://www.aging-us.com/article/205537/text

  Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. […] The information coming from understanding the pathogenesis of the syndromes has proven to be of great value in the research of normal aging. For instance, the identification that loss of DNA repair in multiple disease leads to premature aging has contributed to adding genomic instability as a hallmark of aging. […] However, what constitutes a progeria is not well defined and there are few tools to identify a progeroid patient. […] In this study, we have utilized phenome explorations to define the phenotypes associated with progerias and to develop tools to diagnose patients and identify new progeroid syndromes. […] This allowed us to define the average phenotypes (the progeria phenome) of the progeroid patients and compare it with diseases that have been associated with premature aging (mitochondrial, autophagy and DNA repair disorders). […] In conclusion, progeroid syndromes therefore seem to share most phenotypes with DNA-repair syndromes as shown previously in our hierarchical cluster and networks.

• #78 A new study reveals a key mechanism driving atherosclerosis in Hutchinson-Gilford Progeria Syndrome – Biotech Spain

  https://biotech-spain.com/en/articles/a-new-study-reveals-a-key-mechanism-driving-atherosclerosis-in-hutchinson-gilford-progeria-syndrome/

  Our study represents an important advance in understanding the mechanisms behind vascular aging in HGPS. […] The insights we’ve gained from studying HGPS can help us gain a better understanding of the aging process in general and of the factors that contribute to cardiovascular disease in older individuals.

• #79 Defining the progeria phenome | Aging

  https://www.aging-us.com/article/205537/text

  Progeroid disorders are a heterogenous group of rare and complex hereditary syndromes presenting with pleiotropic phenotypes associated with normal aging. […] The information coming from understanding the pathogenesis of the syndromes has proven to be of great value in the research of normal aging. For instance, the identification that loss of DNA repair in multiple disease leads to premature aging has contributed to adding genomic instability as a hallmark of aging. […] However, what constitutes a progeria is not well defined and there are few tools to identify a progeroid patient. […] In this study, we have utilized phenome explorations to define the phenotypes associated with progerias and to develop tools to diagnose patients and identify new progeroid syndromes. […] This allowed us to define the average phenotypes (the progeria phenome) of the progeroid patients and compare it with diseases that have been associated with premature aging (mitochondrial, autophagy and DNA repair disorders). […] In conclusion, progeroid syndromes therefore seem to share most phenotypes with DNA-repair syndromes as shown previously in our hierarchical cluster and networks.

• #80 A-type lamins and Hutchinson-Gilford progeria syndrome: pathogenesis and therapy

  https://repisalud.isciii.es/entities/publication/bbc2d49d-12b0-44ed-9f18-20074b1cdada

  Lamin A and lamin C (A-type lamins, both encoded by the LMNA gene) are major components of the mammalian nuclear lamina, a complex proteinaceous structure that acts as a scaffold for protein complexes that regulate nuclear structure and function. Abnormal accumulation of farnesylated-progerin, a mutant form of prelamin A, plays a key role in the pathogenesis of the Hutchinson-Gilford progeria syndrome (HGPS), a devastating disorder that causes the death of affected children at an average age of 13.5 years, predominantly from premature atherosclerosis and myocardial infarction or stroke. […] Therefore, understanding how this mutant form of lamin A provokes HGPS may shed significant insight into physiological aging. In this review, we discuss recent advances into the pathogenic mechanisms underlying HGPS, the main murine models of the disease, and the therapeutic strategies developed in cellular and animal models with the aim of reducing the accumulation of farnesylated-progerin, as well as their use in clinical trials of HGPS.

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