Materiały źródłowe

• #1 Angelman Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560870/

  Angelman syndrome is a rare disorder caused by loss of function of the maternal UBE3A. […] One of the causes of AS was found in 1987 through high-resolution chromosome banding technique, which revealed de novo microdeletions in the long arm of chromosome 15 in the region 11-13 (15q11-13). Later it was shown that there are multiple mechanisms other than deletions that can cause AS involving the region 15q11-13. We know now that the primary cause of Angelman syndrome is a selective loss of function of ubiquitin-ligase E3A(UBE3A) in the brain, which is usually expressed maternally. […] Angelman syndrome (AS) is caused by a pathologic lack of expression of the UBE3A gene on the maternal chromosome in combination with physiologic genomic imprinting or silencing on the paternal chromosome in neurons. UBE3A gene is an example of an imprinted gene because it is expressed in a parent of origin-specific manner.

• #2 Understanding the Pathogenesis of Angelman Syndrome through Animal Models

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3399338/

  Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, lack of speech, ataxia, susceptibility to seizures, and unique behavioral features such as easily provoked smiling and laughter and autistic features. The disease is primarily caused by deletion or loss-of-function mutations of the maternally inherited UBE3A gene located within chromosome 15q11-q13. The UBE3A gene encodes a 100kDa protein that functions as ubiquitin ligase and transcriptional coactivator. Emerging evidence now indicates that UBE3A plays a very important role in synaptic function and in regulation of activity-dependent synaptic plasticity. A number of animal models for AS have been generated to understand the disease pathogenesis. The most widely used model is the UBE3A-maternal-deficient mouse that recapitulates most of the essential features of AS including cognitive and motor abnormalities.

• #3 Angelman Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17553

  Angelman syndrome is a rare neurogenic disorder. It is a classic example of genomic imprinting, where the expression of a genomic region differs depending on the chromosome’s parent of origin. AS is a neurodevelopmental disorder affecting mostly the nervous system that manifests with intellectual and developmental disabilities, a puppet-like ataxic movement and phenotype, as well as sleep disorders, and hyperactivity. […] One of the causes of AS was found in 1987 through high-resolution chromosome banding technique, which revealed de novo microdeletions in the long arm of chromosome 15 in the region 11-13 (15q11-13). Later it was shown that there are multiple mechanisms other than deletions that can cause AS involving the region 15q11-13. We know now that the primary cause of Angelman syndrome is a selective loss of function of ubiquitin-ligase E3A(UBE3A) in the brain, which is usually expressed maternally.

• #3 Angelman Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17553

  Angelman syndrome (AS) is caused by a pathologic lack of expression of the UBE3A gene on the maternal chromosome in combination with physiologic genomic imprinting or silencing on the paternal chromosome in neurons. UBE3A gene is an example of an imprinted gene because it is expressed in a parent of origin-specific manner. The paternal UBE3A gene is imprinted mainly in the neurons and has some level of expression in the rest of the body. […] AS is typically caused by a sporadic de novo mutation on the maternal gene UBE3A (part of the ubiquitin pathway) at chromosome 15q11-13. Around 70 to 75% of cases arise from maternal deletion within chromosome 15q11-q13, containing this gene. Approximately 2% to 3% can be due to paternal uniparental disomy (UPD), imprinting center defect (3% to 5%), or single gene point mutation in the maternal UBE3A allele (5 to 10%).

• #4 Angelman Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560870/

  The findings of Angelman syndrome (AS) are mostly limited to the nervous system because physiologically paternal UBE3A is only imprinted in the brain. So if there is a pathologic loss of function mutation of maternal UBE3A, mainly the brain is affected. […] UBE3A codes for a ubiquitin ligase called E6-associated protein (E6-AP). E6-AP is critical for the functioning of the ubiquitin-proteasome pathway, which is essential for the normal functioning of neurons and synaptic plasticity. Loss of function mutation of E6-AP causes impaired ubiquitin-proteasome degradation of many proteins. […] There are mainly four mechanisms that cause loss of function of UBE3A. These are deletion, mutation, imprinting, and uniparental disomy. […] The most severe symptoms are seen in the deletion subtype, out of which class 1 has the worst clinical phenotype. These include global developmental delay, microcephaly, and seizures, no speech, and oculocutaneous hypopigmentation. Increased susceptibility to seizures is seen since some of the GABA genes are deleted in deletion mutations.

• #5 Genetics of AS – Angelman Syndrome Foundation

  https://www.angelman.org/what-is-as/genetics-of-angelman-syndrome/

  Angelman syndrome is caused by a problem with the UBE3A gene located at the 15th chromosome. It’s important to keep in mind that in typical humans, the UBE3A gene from our father is silent and the brain uses the UBE3A gene from our mother during development. […] There are 4 ways that Angelman syndrome can occur. These are called genotypes. Each genotype has a different mechanism that results in AS. […] The most common (70% of cases of AS) and occurs when the mother’s copy of UBE3A has been deleted and is not present. […] (11% of cases of AS) occurs when there is a mutation or alteration in the 15th chromosome inherited from the mother. This mutation or alteration either prevents the expression of UBE3A or alters its function. […] 6% of cases of AS occurs when there is an abnormality in the imprinting center of the 15th chromosome inherited from the mother. The imprinting center is the area of the chromosome that controls whether genes are turned on or off. So, even though UBE3A from the mother may be present, the problem in the imprinting center makes the UBE3A gene unavailable to the brain.

• #6 Unmet clinical needs and burden in Angelman syndrome: a review of the literature | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-017-0716-z

  Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by lack of expression of the maternal ubiquitin-protein ligase E3A (UBE3A) gene in the brain. There are 4 known etiologies of AS responsible for the silencing of the UBE3A gene: deletion in chromosome 15q11-q13 (70% of cases), paternal uniparental disomy (UPD; 2% of cases), imprinting defect (3% of cases), and point mutation (10% of cases). As a result of missing UBE3A in the brain, individuals with AS have severe to profound intellectual disability (ID), lack of speech, difficulties with motor control and planning, significant sleep difficulties, seizures, and unique behavioral features. There are currently no AS-specific systematic treatment approaches; treatment and management is symptomatic with no therapy that addresses the underlying etiology.

• #7 Angelman syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/angelman-syndrome/

  Many of the characteristic features of Angelman syndrome result from the loss of function of a gene called UBE3A. People normally inherit one copy of the UBE3A gene from each parent. Both copies of this gene are turned on (active) in most of the body’s tissues. However, in nerve cells (neurons) in the brain and spinal cord (central nervous system), only the copy inherited from a person’s mother (the maternal copy) is active. This parent-specific gene activation is caused by a phenomenon called genomic imprinting. If the maternal copy of the UBE3A gene is lost because of a chromosomal change or a gene variant (also known as a mutation), a person will have no active copies of the gene in most parts of the brain. […] Several different genetic mechanisms can inactivate or delete the maternal copy of the UBE3A gene. Most cases of Angelman syndrome (about 70 percent) occur when a segment of the maternal chromosome 15 containing this gene is deleted. In other cases (about 10 to 20 percent), Angelman syndrome is caused by a variant in the maternal copy of the UBE3A gene.

• #8

  https://omim.org/entry/105830

  A number sign (#) is used with this entry because 4 known genetic mechanisms can cause Angelman syndrome (AS). Approximately 70% of AS cases result from de novo maternal deletions involving chromosome 15q11.2-q13; approximately 2% result from paternal uniparental disomy of 15q11.2-q13; and 2 to 3% result from imprinting defects. A subset of the remaining 25% are caused by mutations in the gene encoding the ubiquitin-protein ligase E3A gene (UBE3A; 601623) (Kishino et al., 1997). […] Angelman syndrome results from a lack of maternal contribution from chromosome 15q11-q13, arising from de novo deletion in most cases or from uniparental disomy in rare cases. […] Approximately 70% of cases of Angelman syndrome result from de novo maternal deletions involving the 15q11.2-q13 critical region (Kishino et al., 1997).

• #9 2011 Group Project 7 – Embryology

  https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_7

  Extent of microcephaly in 20 AS patients with deletion and without deletion. All AS patients show differing extents of cognitive impairment, movement disorder, characteristic behaviours and difficulty in speech and language. However, there seems to be some phenotype-genotype correlations: […] – 5-7Mb deletions result in the most severe phenotypes such as microcephaly, more severe epilepsy and seizures, motor difficulties and language impairment. AS patients with large deletions also present with clinical hypopigmentation, light hair and eye colour due to the close association of OCA2 gene with UBE3A. Individuals under this category have in general no increased BMI. This is indicated by the graph on the left, which shows more cases of AS patients with deletions having larger deviations from the mean head circumference measurement than non-deletion AS patients.

• #10 Genotype–Phenotype Correlations in Angelman Syndrome

  https://www.mdpi.com/2073-4425/12/7/987

  Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin–protein ligase E3A (UBE3A) on the chromosome 15q11–13 region. […] There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11–q13, paternal uniparental disomy of chromosome 15q11–q13, imprinting defects, and maternally inherited UBE3A mutations. […] The pathogenesis of AS is similar to PWS. UBE3A is a maternally expressed gene: the unmethylated maternal allele is expressed, and the methylated paternal allele is repressed. […] Any genetic causes leading to a non-functional UBE3A protein will result in a knockout of neuronal UBE3A and lead to AS. […] Lack of UBE3A protein expression in the brain of children with AS can lead to abnormal ubiquitination in Purkinje cells in the cerebellum.

• #11 Angelman syndrome (AS, MIM 105830) | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg200967

  Angelman syndrome (AS) is a distinct neurogenetic syndrome, first described in 1965. […] Different underlying genetic mechanisms may cause AS, with deletion of chromosome 15 as the most frequent cause. […] Different genetic mechanisms may cause AS, such as deletion of the 15q11.2-q13 critical region (6075%), paternal uniparental disomy (25%), imprinting defect (25%) and mutation in the UBE3A gene (10%). […] Different underlying genetic mechanisms may cause AS resulting in a comparable clinical phenotype with severe mental retardation, speech retardation and behavioural phenotype. However, differences in the clinical phenotype are observed in AS patients, with a different underlying genetic mechanism. […] A deletion or re-arrangement of the maternal chromosome 15 at locus 15q11-q13 is present in 6075% of the patients. Patients with a deletion have a more severe clinical phenotype including microcephaly, motor difficulties, seizures and language impairment.

• #12 Angelman syndrome-associated ubiquitin ligase UBE3A/E6AP mutants interfere with the proteolytic activity of the proteasome | Cell Death & Disease

  https://www.nature.com/articles/cddis2014572

  Angelman syndrome, a severe neurodevelopmental disease, occurs primarily due to genetic defects, which cause lack of expression or mutations in the wild-type E6AP/UBE3A protein. […] Interestingly, most of these mutations are catalytically defective, thereby indicating the importance of UBE3A enzymatic activity role in the Angelman syndrome pathology. […] Our results suggest that mutated catalytically inactive forms of UBE3A may cause defects in overall proteasome function, which could have an important role in the Angelman syndrome pathology. […] The principal protein affected in AS is the E3 ubiquitin ligase E6-associated protein (E6AP/UBE3A), the gene being found on chromosome 15q11-13. […] The majority of these mutations however are defective in ubiquitin ligase activity, indicating that the loss of enzymatic activity of UBE3A is important in promoting the development of AS.

• #13 Angelman syndrome: A genetic challenge for physical and learning disabilities – American Journal of Biopharmacy and Pharmaceutical Sciences

  https://ajbps.org/angelman-syndrome-a-genetic-challenge-for-physical-and-learning-disabilities/

  Angelman syndrome (AS) was first reported in 1965 by Dr. Harry Angelman. The cause of AS is a lack of production by maternal imprinted genes (UBE3A) on the 15q11-q13 chromosome. On cytogenetic analysis, at least 5060% of patients had a maternally induced de novo mutation of chromosome 15q11-13 with more serious clinical phenotypes such as microcephaly, seizures, language impairment, and motor difficulties. One of three mechanisms of AS is present, if there is any abnormality in DNA methylation: (a) UPD, (b) large common deletion, and (c) IC deletion. If there is an abnormality in DNA methylation, further examinations are recorded to confirm the distinct genetic process. In those cases, the common later one is to achieve microsatellite, fluorescent in situ hybridisation (FISH) or microarray chromosome study to find out whether 15q11.2-q13 is deleted. A fraction of individuals with defects in imprinting caused by the IC and with a bipartite structure and managing cis imprint resetting and maintain with 15q11.2-q13 imprint domain. Without any changes in the DNA frequency and primary epimutation, imprinting defects could be found. Protein truncating mutation is the most found UBE3A mutation in AS and reported in more than 60 mutations. Frameshift mutation is also found in around 6070% of AS. Missense and nonsense mutation is found in approximately 25% with gross deletions, splicing defects, and complex rearrangements. Multiexonic or whole gene deletion is identified by array-CGH in some cases and laboratory and methodology may vary such deletions.

• #14 Angelman syndrome: review of clinical and molecular aspects | TACG

  https://www.dovepress.com/angelman-syndrome-review-of-clinical-and-molecular-aspects-peer-reviewed-fulltext-article-TACG

  Mechanisms of controlling gene expression include DNA insulators, histone modifications, DNA methylation, and transcriptional enhancer competition. […] Deficits in the imprinted gene cluster on chromosome 15q11-13 cause Prader-Willi syndrome (PWS) and AS. […] Loss of expression of maternally derived UBE3A causes AS, while loss of expression of paternally derived gene(s) causes PWS. […] The ICR for the 15q11-q13 cluster has been designated the IC. […] The IC regulates in cis the establishment and maintenance of the imprint for the entire cluster. […] UBE3A itself is not differentially methylated; its imprinted expression is indirectly regulated by a long non-coding antisense RNA transcript (UBE3A-ATS) which is part of a larger SNURF-SNRPN transcript. […] Changes in DNA methylation and histone acetylation of the PWS-IC control production of the UBE3A-ATS from the paternal allele.

• #14 Angelman syndrome: review of clinical and molecular aspects | TACG

  https://www.dovepress.com/angelman-syndrome-review-of-clinical-and-molecular-aspects-peer-reviewed-fulltext-article-TACG

  Angelman syndrome (AS) is due to deficient expression of the ubiquitin protein ligase E3A (UBE3A) gene, which displays paternal imprinting. […] Much remains to be understood regarding how insufficiency of E6-AP, the protein product of UBE3A, results in the observed neurodevelopmental deficits. […] The molecular pathogenesis of how UBE3A deficiency leads to this phenotype is beginning to be clarified. […] AS is caused by a lack of expression of the maternally inherited UBE3A gene in the brain. […] UBE3A is one of a small subset of human genes that are imprinted that is, expressed depending on parent of origin, in a tissue-specific manner. […] Establishing brain-only imprinting of UBE3A in mice resurrected UBE3A’s status as a candidate gene for AS. […] AS is caused by deficient expression of the maternal copy of the UBE3A gene due to one of four molecular etiologies: deletion of the AS critical region on maternal chromosome 15q11-q13, paternal uniparental disomy (UPD) for chromosome 15, an imprinting defect causing lack of expression of the maternal copy of UBE3A, and mutations in the maternally inherited copy of UBE3A.

• #15 Angelman Syndrome, a Genomic Imprinting Disorder of the Brain | Journal of Neuroscience

  https://www.jneurosci.org/content/30/30/9958

  Loss of the active maternal UBE3A allele in AS is caused, in the majority of cases (75%), by maternal deletion of the chromosome 15q11-q13 region that contains UBE3A (Lossie et al., 2001). Another 20% of AS cases result from mutations of the maternal UBE3A allele (Kishino et al., 1997; Matsuura et al., 1997). […] The imprinting process marks a relatively small number (100-200) of human genes and occurs in the germline. […] The CG-rich imprinting region in chromosome 15q11-q13 is a 300 bp segment (Zeschnigk et al., 1997) that is called the Prader-Willi syndrome imprinting center (PWS-IC) (Fig. 2). […] The PWS-IC is located in the upstream promoter region of the SNURF/SNRPN transcript (Sutcliffe et al., 1994; Zeschnigk et al., 1997; Bielinska et al., 2000; El-Maarri et al., 2001). […] Although the PWS-IC is the master regulator of imprinting of the chromosome 15q11-q13 region, transcriptional repression of the paternal UBE3A allele involves additional brain-specific molecular mechanisms that remain to be conclusively elucidated (Fig. 2B).

• #15 Angelman Syndrome, a Genomic Imprinting Disorder of the Brain | Journal of Neuroscience

  https://www.jneurosci.org/content/30/30/9958

  Mapping of the AS genetic locus to the long arm of chromosome 15 between bands q11 and q13 (15q11-q13) was first reported in 1987 (Magenis et al., 1987) and confirmed in additional patients displaying chromosome 15q11-q13 deletions (Knoll et al., 1989). AS was only observed when the deletion occurred on the copy of chromosome 15 that was inherited from the mother (Knoll et al., 1989). […] The specific gene in 15q11-q13 that causes AS encodes ubiquitin protein ligase E3A (UBE3A). UBE3A is also known as E6-associated protein (E6-AP) because it was originally discovered as a binding partner of the E6 protein of the human papilloma virus (Huibregtse et al., 1991, 1993). […] In AS, the maternal UBE3A allele is absent or inactivated and, as a result, there is no active copy of UBE3A in neurons.

• #16 Genetics of AS – Angelman Syndrome Foundation

  https://www.angelman.org/what-is-as/genetics-of-angelman-syndrome/

  3% of cases of AS occurs when there are two, number 15 chromosomes from the father, but not one from the mother. Since the UBE3A from the father is silenced or turned off, and the one from the mother is absent, the brain cannot get the information it needs from UBE3A. […] Unfortunately, the most common AS genotype, deletion positive, tends to be the most severe, in terms of symptoms or characteristics.

• #17 Angelman syndrome: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/angelman-syndrome/

  In a small percentage of cases, Angelman syndrome results when a person inherits two copies of chromosome 15 from his or her father (paternal copies) instead of one copy from each parent. This phenomenon is called paternal uniparental disomy. Rarely, Angelman syndrome can also be caused by a chromosomal rearrangement called a translocation, or by a variant or other defect in the region of DNA that controls activation of the UBE3A gene. These genetic changes can abnormally turn off (inactivate) UBE3A or other genes on the maternal copy of chromosome 15. […] The causes of Angelman syndrome are unknown in 10 to 15 percent of affected individuals. Changes involving other genes or chromosomes may be responsible for the disorder in these cases.

• #18 Angelman syndrome (AS, MIM 105830) | European Journal of Human Genetics

  https://www.nature.com/articles/ejhg200967

  A small percentage of patients (25%) have paternal UPD for chromosome 15. […] Mutations in the imprinting centre (IC) (imprinting centre defect) are present in about 25% of the patients. […] The UBE3A gene shows biallelic expression in most tissues, but shows preferential expression of the maternal allele in the brain of humans and mice. […] Mutations in the UBE3A gene results in a disrupted functioning of the protein and could cause the mental retardation and seizures.

• #19 2011 Group Project 7 – Embryology

  https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_7

  – AS patients with uniparental disomy (UPD) have better physical growth, fewer motor deficits and lower seizure occurrences. […] – Individuals with AS resulting from imprinting defects have the least debilitating features, such as higher developmental and language ability than AS caused by other mechanisms. […] – The Body Mass Index (BMI) of 33% of the UBE3A mutation patients, and 4764% of the patients from the classes II (UPD) and III (Imprinting defect) is above the 95th centile. […] Drosophila (common fruit fly) is an excellent model to use for better understanding of genetic diseases in humans as they are highly homologous to human UBE3A (hUBE3A), illustrating a high evolutionary conservation. Studies using the Drosophila model have shown that the functional absence of UBE3A resulted in decreased morphogenesis of dendritic branches. This is of interest as dendritic branches cover over 90% of the neuronal surface where synapse between neurons occur. Proper formation and maturation of dendritic spines is also required so they come in contact with other neurons for effective transmission of neuronal signals. Thus proper formation of dendritic branching is pivotal for effective neuronal function and hence cognitive function. Interestingly, overexpression of dUBE3A also gave the same result, consisting of abnormal locomotion and decreased dendritic branching in sensory neurons. This suggests a possible research field for some forms of autism where the region containing UBE3A is duplicated, leading to delayed motor skills and seizures.

• #20 Angelman syndrome – Wikipedia

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

  Angelman syndrome is due to a lack of function of part of chromosome 15, typically due to a new mutation rather than one inherited. Most often it is due to a deletion or mutation of the UBE3A gene on that chromosome. […] The paternal copy of UBE3A is inactivated through a process known as imprinting and the fetus relies on the functioning maternal copy of UBE3A in order to develop normally. In an individual with AS, however, the maternal UBE3A gene is absent or not functioning normally. This can be due to genetic errors such as the deletion or mutation of a segment of chromosome 15, uniparental disomy, or translocation. While Angelman syndrome can be caused by a single mutation in the UBE3A gene, the most common genetic defect leading to Angelman syndrome is a 5- to 7-Mb (megabase) maternal deletion in chromosomal region 15q11.2-q13.

• #21 Angelman syndrome – Wikipedia

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

  Specifically, the paternal copy of UBE3A is known to be imprinted within the hippocampus, cortex, thalamus, olfactory bulb, and cerebellum. Therefore, in these areas of the brain, a functioning maternal copy of UBE3A is essential for proper development. […] Region 15q11-13 is implicated in both Angelman syndrome and Prader-Willi syndrome (PWS). While AS results from mutation, loss or abnormal imprinting involving the UBE3A gene within this region on the maternal chromosome, loss of a different cluster of genes within the same region on the paternal chromosome causes PWS.

• #22 Truncation of Ube3a-ATS Unsilences Paternal Ube3a and Ameliorates Behavioral Defects in the Angelman Syndrome Mouse Model | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1004039

  Disruption of the maternal allele, through genomic deletion, paternal uniparental disomy, imprinting defects, or point mutations, leads to the absence of UBE3A expression in neuronal tissues and hence Angelman syndrome. […] One could speculate that by correcting the expression level of UBE3A via activating the silenced paternal allele, the disease might be treated. […] Imprinting of UBE3A, however, is not associated with differential DNA methylation at the promoter region. […] Instead, it is regulated by its antisense RNA, UBE3A-ATS, which is expressed from the paternally inherited chromosome in the brain. […] Recently, by terminating Ube3a-ATS transcription in neuronally differentiated ES cells, we have showed that paternal Ube3a can be activated to a comparable level as maternal Ube3a, suggesting a direct role of Ube3a-ATS in suppressing paternal Ube3a.

• #23

  https://link.springer.com/article/10.1007/s13311-021-01082-x

  There is a strong correlation between loss of the E6-AP ligase activity and AS as well as numerous protein targets involved in cell proliferation and survival, synaptic function, cell signaling, and nervous system development that have been identified as UBE3A substrates. […] Moreover, UBE3A expression is correlated with the regulation of various genes involved in protein catabolism, cell cycle, brain morphology, and transcriptional regulation. […] The exact method of how paternal UBE3A is silenced through UBE3A-ATS is not fully understood; however, several mechanisms have been suggested including a transcriptional interference mechanism where RNA polymerases of the UBE3A-ATS and the gene conflict and disrupt transcription and a RNA interference mechanism where double-stranded RNA forms between the sense and antisense RNAs.

• #24 2011 Group Project 7 – Embryology

  https://embryology.med.unsw.edu.au/embryology/index.php?title=2011_Group_Project_7

  It is also known that UBE3A plays an important role in synaptic transmission, but exactly how it does so is still not completely understood. […] UBE3A is a member of the E3 ubiquitin ligase family of enzymes. It is responsible for the addition of ubiquitin to the target protein for degradation of the ubiquitinated protein. These processes are required for normal human cognitive function. In this way synaptic protein Arc (activity-regulated cytoskeleton-associated protein) is degraded to control synaptic function. Arc is a target protein of UBE3A in dendritic spines found in the hippocampal neurons. Deletion of UBE3A leads to the accumulation of Arc in neurons leading to trafficking of AMPA ( -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, resulting in impaired cognitive functions.

• #25 Prader-Willi and Angelman syndromes: mechanisms & management | TACG

  https://www.dovepress.com/prader-willi-and-angelman-syndromes-mechanisms-and-management-peer-reviewed-fulltext-article-TACG

  UBE3A is subject to genomic imprinting, with preferential maternal-specific expression in brain and, more specifically, in neurons but not in glia. […] The disruption of UBE3A activity leads to inappropriately high levels of these target proteins and consequent neuronal dysfunction. […] UBE3A, encodes a HECT (homologous to the E6-AP carboxyl terminus) domain E3 ubiquitin ligase that catalyzes the addition of ubiquitin to lysine residues on substrate proteins, leading to the degradation of the ubiquitinated substrate protein. […] Despite the critical role that UBE3A plays in human cognitive function and evidence of clinical neurological and behavioral phenotype through mouse model studies, relatively little is known about UBE3As role in human nervous system development or how the mutated UBE3A expression leads to the cognitive and language impairment underlying AS.

• #26 Understanding the Pathogenesis of Angelman Syndrome through Animal Models

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3399338/

  Lately, there have been major advancements in understanding the molecular basis of the cognitive deficits associated with AS. […] The absence of UBE3A plays a crucial role in the postnatal experience driven period. […] UBE3A mRNA and protein levels are regulated by synaptic activity. […] UBE3A regulates the surface expression of AMPARs through ubiquitination and proteasomal degradation of Arc. […] The UBE3A protein was found in the pre and postsynaptic compartments and was localized in the growth cones of hippocampal neurons in primary culture. […] UBE3A is shown to interact with and coactivate nuclear steroid hormone receptors. […] It is evident from the existing literature that the loss of expression of maternal-inherited UBE3A is primarily responsible for AS, although we cannot completely rule out the possibility of other disease-modifying genes like GABRB3. Dysfunction of UBE3A is sufficient to produce phenotypes resembling AS in different animal models.

• #27 Angelman Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17553

  The findings of Angelman syndrome (AS) are mostly limited to the nervous system because physiologically paternal UBE3A is only imprinted in the brain. So if there is a pathologic loss of function mutation of maternal UBE3A, mainly the brain is affected. […] UBE3A codes for a ubiquitin ligase called E6-associated protein (E6-AP). E6-AP is critical for the functioning of the ubiquitin-proteasome pathway, which is essential for the normal functioning of neurons and synaptic plasticity. Loss of function mutation of E6-AP causes impaired ubiquitin-proteasome degradation of many proteins. Many targets of E6-AP that have been identified are p53, p27, Arc, and ephexin5. […] Mouse models of AS with UBE3A knockout of the maternal gene have shown ataxia, seizures, decreased size of the brain, motor abnormalities. These models have also demonstrated deficits in hippocampal long term potentiation (LTP), which explains deficits in memory and learning in AS patients.

• #28 Understanding the Pathogenesis of Angelman Syndrome through Animal Models

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3399338/

  UBE3A gene was suggested as a strong candidate for autism because of its imprinted nature and maternal dominance. […] UBE3A is also demonstrated to act as a transcriptional coactivator of steroid hormone receptors. UBE3A is shown to interact with a number of cellular proteins that indicate its involvement in multiple cellular functions including cell cycle regulation, synaptic function and plasticity, and cellular protein quality control. […] The most widely used model of AS is the UBE3A knockout mice. This mouse was generated by a deletion mutation in exon 2 of UBE3A gene thereby inhibiting the formation of a functionally active protein. […] The maternal deficient heterozygous mice UBE3A m/p+ exhibited reduced brain weight, ataxia, motor impairment, and abnormal EEG pattern. […] The UBE3A m/p+ mice showed reduced number of dopaminergic neurons in the substantia nigra accompanied by poor performance in behavioral paradigms sensitive to nigrostriatal dysfunction.

• #29 Angelman Syndrome, a Genomic Imprinting Disorder of the Brain | Journal of Neuroscience

  https://www.jneurosci.org/content/30/30/9958

  The recent identification of activity-regulated, cytoskeletal-associated protein (ARC) as a target of ubiquitylation by UBE3A, provides a tantalizing prospect for the primary neuronal defect underlying AS (Greer et al., 2010). […] The great majority of UBE3A mutations that lead to AS are predicted to disrupt or delete the 350 aa C-terminal HECT (homologous to the E6-AP C terminus) domain (Lossie et al., 2001). […] Given the likelihood that the accumulation of such target proteins underlies the AS disease mechanism, there is great interest in identifying the protein targets that are ubiquitinated by UBE3A in neurons.

• #30 Investigating the Causal Role of Arc in Angelman Syndrome Pathogenesis – Angelman Syndrome Foundation

  https://www.angelman.org/research/investigating-the-causal-role-of-arc-in-angelman-syndrome-pathogenesis/

  Investigating the Causal Role of Arc in Angelman Syndrome Pathogenesis. Previous research discoveries have indicated that one of the UBE3A target proteins, Arc (activity-regulated cytoskeleton-associated protein) plays a critical role in regulating synaptic plasticity and long-term information storage in the brain. […] By understanding how Arc is involved in learning and memory in the context of Angelman syndrome (AS) and how it is regulated in the Arc-dependent process, this research has the possibility to lead to development of approaches for therapeutic interventions that target the learning and memory deficits in AS.

• #31 Angelman Syndrome | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/17553

  There are mainly four mechanisms that cause loss of function of UBE3A. These are deletion, mutation, imprinting, and uniparental disomy. […] The most severe symptoms are seen in the deletion subtype, out of which class 1 has the worst clinical phenotype. These include global developmental delay, microcephaly, and seizures, no speech, and oculocutaneous hypopigmentation. Increased susceptibility to seizures is seen since some of the GABA genes are deleted in deletion mutations. The deletion of OCA1 genes in combination with the regulatory effect of UBE3A on MC1R might explain oculocutaneous hypopigmentation.

• #32 Angelman Syndrome > Fact Sheets > Yale Medicine

  https://www.yalemedicine.org/conditions/angelman-syndrome

  Certain mutations in the maternal copy of the UBE3A gene, which account for about 10% to 20% of cases. […] Paternal uniparental disomy (UPD) of chromosome 15, which accounts for around 3% to 7% of Angelman syndrome cases. […] Imprinting center defects on chromosome 15, which account for 3% to 5% of cases of Angelman syndrome. The imprinting center determines which genes are imprinted, or turned off. In some cases, a mutation or other problem in the imprinting center of chromosome 15 causes the maternal copy of the UBE3A gene to be turned off and thereby inactive, resulting in Angelman syndrome. […] The symptoms and features of Angelman syndrome may vary based on the genetic mechanism that causes the condition. […] In rare cases, with a partial genetic deficiency of UBE3A due to mosaic mutations of UBE3A or an imprinting mutation, their presentations are significantly milder.

• #33 In Angelman, increases seen in pathway for clearing cellular waste | Cell, mouse models shed new light on mechanism of disease | Angelman Syndrome NewsEnvelope icon

  https://angelmansyndromenews.com/news/cell-mouse-models-angelman-shed-light-disease-mechanism-autophagy/

  Increases in autophagy, a pathway for clearing cellular waste, were observed in cell and mouse models of Angelman syndrome (AS) in a recent study that revealed new details of this disease mechanism. […] Researchers noted that it isn’t yet clear whether this increase is a compensatory process to help restore more normal brain function, or if it’s part of the disease-driving processes. […] Angelman syndrome is a complex neurological disorder caused by a missing or dysfunctional copy of the UBE3A gene that people normally inherit from their mothers. […] UBE3 is responsible for producing the UBE3A protein, a key player in the ubiquitin-proteasome system, called UPS, which degrades unneeded or damaged proteins. […] Another way of getting rid of cellular waste is through autophagy, wherein waste is transported into cell compartments called lysosomes for recycling.

• #34 In Angelman, increases seen in pathway for clearing cellular waste | Cell, mouse models shed new light on mechanism of disease | Angelman Syndrome NewsEnvelope icon

  https://angelmansyndromenews.com/news/cell-mouse-models-angelman-shed-light-disease-mechanism-autophagy/

  However, its role in Angelman hasn’t been established. […] Markers of increased autophagy were observed in the cell model relative to normal cells. […] Importantly, evidence suggested that both the initiation of autophagy as well as its degradative activity were elevated in the AS samples. […] Together, these results indicate that UBE3A deficiency increases autophagy activity, the researchers wrote. […] A particularly notable finding was an elevation in an active form AMPK in AS mice relative to healthy mice. […] Levels of active ULK1 were similarly elevated in AS mice, overall suggesting that the activation of AMPK and ULK1 may be central to the observed increases in autophagy, according to the researchers. […] Another protein called p53, which both positively and negatively regulates autophagy, was found to have a non-significant increase in its levels in the nucleus, or core, of cells from AS mice.

• #35 Investigating Ube3a-dependent sumoylation imbalance in the pathogenesis of the Angelman syndrome and autism

  https://www.fondazionetelethon.it/en/what-we-do/research/projects-funded/investigating-ube3a-dependent-sumoylation-imbalance-in-the-pathogenesis-of-the-angelman-syndrome-and-autism-2/

  Neurodevelopmental and psychiatric disorders affect millions of people in the world and are a major socio-economic burden. […] Loss of UBE3A causes the Angelman syndrome (AS), characterized by developmental delay, speech impairments, intellectual disability and epilepsy, while duplications and triplications of UBE3A chromosomal locus are the most common cytogenetic events associated with Autism Spectrum Disorders (ASD). […] The pathophysiology of these disorders remains largely unclear and an effective treatment is lacking. […] We take an interdisciplinary approach that integrates the use of a wide range of genetic tools with proteomics and advanced imaging to dissect the pathological mechanism of AS and ASD. […] We anticipate that the innovative and original nature of this research program will uncover novel pathogenic insights into the development of AS and ASD and hopefully offer new therapeutic perspectives to treat these as yet incurable diseases.

• #36 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20230914/Study-reveal-how-a-causal-factor-in-Angelman-syndrome-eliminates-neural-chat.aspx

  Researchers from the University of Tokyo reveal how the presynaptic Ube3a E3 ligase, a causal factor in Angelman syndrome, eliminates neural chat. […] Furusawa and his team hoped to reveal the molecular mechanism involved in synaptic elimination during neural development and offer insights into developmental disorders such as Angelman syndrome. […] In patients with Angelman syndrome, a gene called Ube3a does not function well, which prevents synapse elimination during development. […] They discovered that Ube3a removes synapses by degrading presynaptic receptors called Bone Morphogenetic Protein (BMP) receptors, which are necessary for synapse formation. […] This is the first study to show that the lack of presynaptic Ube3a E3 ligase disrupts synaptic pruning. […] The finding enabled the team to suggest a new mechanism by which genetic mutations and abnormal Ube3a dosage lead to impaired synaptic transmission and hinder brain maturation.

• #37 Angelman syndrome-associated ubiquitin ligase UBE3A/E6AP mutants interfere with the proteolytic activity of the proteasome | Cell Death & Disease

  https://www.nature.com/articles/cddis2014572

  Studies have demonstrated that ubiquitin ligase activity of UBE3A has a role in the proteasome-dependent degradation of several cellular substrates, and it can be reasoned that defects in the regulation of some of these substrates can contribute to AS development. […] UBE3A can directly ubiquitinate the S5a subunit, and that its Drosophila ortholog, Ube3a, mediates ubiquitination of the Drosophila S5a homolog, resulting in its subsequent degradation. […] We show here that AS-associated UBE3A mutants interact more strongly with S5a, with one of the consequences being a general inhibitory effect on the overall proteolytic activity of the proteasome. […] These results suggest that perturbation of overall proteasome function may be an important element in the development of AS, which thus shows many similarities with other proteasomal neurological defects.

• #38 Angelman syndrome-associated ubiquitin ligase UBE3A/E6AP mutants interfere with the proteolytic activity of the proteasome | Cell Death & Disease

  https://www.nature.com/articles/cddis2014572

  The above results suggest that UBE3A can exert a direct effect on the overall proteolytic activity of the proteasome, probably via its interaction with the S5a subunit. […] In contrast, in each case, the catalytically inactive mutants of UBE3A all had an inhibitory effect on proteasomal activity. […] Ultimately, this suggests the importance of a functional UBE3A for optimal proteasome function, and therefore implies one way in which lack of either the protein (ablated expression) or its function (catalytically inactive mutation) can contribute not only to AS pathogenesis, but possibly also to the pathogenesis of other neurological diseases which occur due to protein aggregation.

• #39 GTX-102 for Angelman Syndrome (AS)—Ultragenyx

  https://www.ultragenyx.com/our-research/pipeline/gtx-102-for-angelman-syndrome/

  AS is caused by loss-of-function or deletion of the maternally inherited allele of the UBE3A gene. […] Therefore, individuals with AS have limited or no UBE3A protein expression in the central nervous system and experience developmental delay, communication impairments, balance issues, motor impairment, anxiety, disturbed sleep and debilitating seizures. […] GTX-102 is an investigational antisense oligonucleotide (ASO) therapy designed to inhibit expression of UBE3A-ATS in order to prevent silencing of the paternally inherited allele of the UBE3A gene and reactivate expression of the deficient protein.

• #40

  https://www.omim.org/entry/105830?search=angelman&highlight=angelman

  A number sign (#) is used with this entry because 4 known genetic mechanisms can cause Angelman syndrome (AS). Approximately 70% of AS cases result from de novo maternal deletions involving chromosome 15q11.2-q13; approximately 2% result from paternal uniparental disomy of 15q11.2-q13; and 2 to 3% result from imprinting defects. A subset of the remaining 25% are caused by mutations in the gene encoding the ubiquitin-protein ligase E3A gene (UBE3A; 601623) (Kishino et al., 1997). […] Approximately 70% of cases of Angelman syndrome result from de novo maternal deletions involving the 15q11.2-q13 critical region (Kishino et al., 1997). […] In patients with Angelman syndrome, caused by deficiency of the maternal copy of the imprinted gene UBE3A (601623), the paternal copy of UBE3A is intact but silenced by a nuclear-localized long noncoding RNA, UBE3A antisense transcript (UBE3AATS, or SNHG14; 616259). Meng et al. (2015) developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3aats with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3aats and sustained unsilencing of paternal Ube3a in neurons in vitro and in vivo. Partial restoration of Ube3a protein in an Angelman syndrome mouse model ameliorated some cognitive deficits associated with the disease. Meng et al. (2015) concluded that they had developed a sequence-specific and clinically feasible method to activate expression of the paternal UBE3A allele.

• #41 Gene Therapy for Angelman Syndrome: Future Trials

  https://cureangelman.org/gene-therapy-for-the-treatment-of-angelman-syndrome-future-clinical-trials

  A virus (adeno-associated virus=AAV) is used to carry (vector) the UBE3A gene into the nerve cells (neuron) of the brain and implant it into the nucleus (manufacturing facility of the cell), so that each cell can make the protein UBE3A (E6-AP ubiquitin ligase) that is coded by UBE3A and is missing in those individuals with Angelman Syndrome (AS). […] The benefit of AAV therapy is that the virus can infect the targeted cell and allow for long-term gene expression. […] Since the UBE3A gene is only missing in neurons due to its imprinted nature and lack of paternal expression, replacing this gene will allow for production of the protein needed for normal cell function (e.g. ubiquitination of various proteins in neurons and at the synapses; as discussed above, to tag proteins for degradation).

• #42 Gene Therapy for Angelman Syndrome: Future Trials

  https://cureangelman.org/gene-therapy-for-the-treatment-of-angelman-syndrome-future-clinical-trials

  The brains of individuals with AS are considered to be morphologically normal, so by giving back this gene and making this protein, the expectation is to restore many of the functions that have been lost. […] In a study published by Dr. Weebers lab (Dailey, et al, 2011), it was found that after the AAV was inserted into the brain of mice, Ube3a expression and E6-AP protein levels were increased and cognition was improved. […] In AS mice, improvements were seen in learning, memory, and neuronal/synaptic plasticity. […] Agilis is proud to announce that they have recently received Orphan Drug status by the FDA. […] Agilis timeline is to optimize the DNA and capsid for humans and select a lead in 2016. […] They are also currently working on Phase I clinical protocol development to find appropriate outcome measures that can be used in the trial to evaluate for clinical efficacy. […] This step is one of the most important for successful clinical trials. […] Agilis is looking into various technologies that may be able to regulate expression.

• #43 Small-Molecule

  https://www.genengnews.com/topics/drug-discovery/small-molecule-unsilencers-show-promise-against-angelman-syndrome/

  Angelman syndrome is caused by mutations in the maternally inherited copy of the UBE3A gene. Paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons. Therefore, when the maternal copy is mutated, UBE3A protein in the brain is eliminated. However, the reactivation of paternal UBE3A is a possible approach for treating AS. […] Now, researchers have identified a small molecule that could be safe, non-invasively delivered, and capable of turning on the dormant paternally-inherited UBE3A gene copy brain-wide, which would lead to proper protein and cell function. […] (S)-PHA533533, a compound that was previously developed as an anti-tumor agent, was found to act “through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice.”

• #44 Researchers identify potential treatment for Angelman syndrome | ScienceDaily

  https://www.sciencedaily.com/releases/2024/07/240708101009.htm

  Angelman syndrome is a rare genetic disorder caused by mutations in the maternally-inherited UBE3A gene and characterized by poor muscle control, limited speech, epilepsy, and intellectual disabilities. […] Researchers have found that children with the conditions are missing the maternally-inherited copy of the UBE3A gene, while the paternally-inherited copy of the UBE3A gene remains dormant in neurons, as it does in neurotypical individuals. Typically, UBE3A helps regulate the levels of important proteins; missing a working copy leads to severe disruptions in brain development. […] For reasons that aren’t fully clear, the paternal copy of UBE3A is normally „turned off” in neurons throughout the entire brain. Thus, when the maternal copy of the UBE3A gene is mutated, this leads to a loss of UBE3A protein in the brain. Philpot and other researchers have theorized that turning on the paternal copy of UBE3A could help treat the condition.

• #45 Small-Molecule

  https://www.genengnews.com/topics/drug-discovery/small-molecule-unsilencers-show-promise-against-angelman-syndrome/

  Researchers were able to confirm the results using induced pluripotent stem cells derived from humans with Angelman syndrome. Additionally, researchers observed that (S)-PHA533533 has excellent bioavailability in the developing brain. The authors add that, “peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression.” […] Although (S)-PHA533533 shows promise, researchers are still working to identify the precise target inside cells that causes the desired effects of the drug. Philpot and colleagues will also conduct further studies to refine the medicinal chemistry of the drug to ensure that the compound—or another version of it—is safe and effective for future use in the clinical setting.

• #46 Researchers identify potential treatment for Angelman syndrome | ScienceDaily

  https://www.sciencedaily.com/releases/2024/07/240708101009.htm

  Researchers genetically modified mouse neural cells with a fluorescent protein that glows when the paternal UBE3A gene is turned on. […] (S)-PHA533533, a compound that was previously developed as an anti-tumor agent, caused neurons to express a fluorescent glow that rivaled that induced by topotecan, meaning that its effect was potent enough to successfully turn on paternal UBE3A. […] Additionally, researchers observed that (S)-PHA533533 has excellent bioavailability in the developing brain, meaning it travels to its target with ease and sticks around. […] Although (S)-PHA533533 shows promise, researchers are still working to identify the precise target inside cells that causes the desired effects of the drug. Philpot and colleagues also need to conduct further studies to refine the medicinal chemistry of the drug to ensure that the compound — or another version of it — is safe and effective for future use in the clinical setting.

• #47 Finding novel treatments for Angelman syndrome: Could Syn3 be the answer?

  https://researchfeatures.com/finding-novel-treatments-angelman-syndrome-could-syn3-answer/

  Abnormalities in neuronal communication is associated with many neurodegenerative diseases, including depression and Angelman syndrome (AS). […] Dr John Marshall, professor at Brown University in the USA, is investigating the mechanism of synaptic dysfunction to develop novel therapies. […] His research focuses on the design of compounds that can activate and restore the strengthening of synaptic connections in AS. […] AS is caused by deficiency of a gene called UBE3A, which is responsible for breaking down proteins during the clear-out processes taking place in cells. […] Abnormalities also stem from reduced brain-derived neurotrophic factor (BDNF) activity. […] Studies by Marshalls group and several others have shown that, similar to the BDNF decrease, disruption in the function of UBE3A in the brain affects the efficiency of neuronal cells to communicate.

• #48 Finding novel treatments for Angelman syndrome: Could Syn3 be the answer?

  https://researchfeatures.com/finding-novel-treatments-angelman-syndrome-could-syn3-answer/

  A line of investigation towards treatment discovery would be to mimic the TrkB and PDS-95 coupling and trigger synapse activation. […] The team tested CN2097 in a mouse model of AS that was generated without the gene UBE3A in neurons to mimic the disease. […] Administration of the compound inhibited the degradation of proteins that take part in the synapse and, therefore, restored synapse activation. […] The team then attempted to check the efficiency of the compound in mouse models of anxiety and depression that show similar abnormalities in synaptic function. […] Treatment with Syn3 in mice with mild stress reversed abnormalities of synaptic function in the hippocampus, restoring the number of synapses as well as the levels of synaptic proteins. […] Considering previous findings that the PSD-95 pathway is implicated in depressive behaviour, Marshall and team evaluated the antidepressant effects of CN2097 in the mouse models of depression and anxiety.

• #49 A phase IIa, multicenter, open-label, 12-week study to in…

  https://genentech-clinicaltrials.com/en/trials/neurodevelopmental-disorder/angelman-syndrome/study-to-investigate-the-pharmacokinetics-and-safety-an-84203.html

  The main cause of AS is a problem with a gene called UBE3A, but sometimes there can be issues with other genes too, including those coding proteins that are necessary to build the GABAA 5 receptor. This receptor plays a major role in the body e.g., in brain development, learning, sleep, and seizure control, among others. Such forms of AS are known as deletion AS. […] Alogabat is designed to help the remaining receptors to perform their function and thus could potentially make up for their reduced number. This may improve various symptoms of AS. […] The first part of the study aims to test how safe alogabat is in children at different doses, and to understand what happens to alogabat once it is in the body. […] The second part of the study aims to test whether alogabat can improve abnormalities in brain activity that are typical for AS. […] Both parts of the study aim to assess how safe alogabat is in children with AS.

• #50 Angelman Syndrome | Boston Children’s Hospital

  https://www.childrenshospital.org/conditions/angelman-syndrome

  Angelman syndrome is caused by a genetic mutation on chromosome 15. The name of this gene is UBE3A. Normally, people inherit one copy of the gene from each parent, and both copies become active in many areas in the body. Angelman syndrome occurs when only one copy of the gene is active in certain areas of the brain. […] Researchers are studying children with Angelman syndrome to determine the highest dose of a new class of drugs called antisense oligonucleotides (ASOs) that can be given without causing serious side effects. It is thought that these drugs can help control some of the neurological and movement difficulties associated with the disorder, such as tremors.

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