Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angelman syndrome is a single-gene disorder characterized by intellectual disability, developmental delay, behavioural uniqueness, speech impairment, seizures and ataxia. It is caused by maternal deficiency of the imprinted gene UBE3A, encoding an E3 ubiquitin ligase. All patients carry at least one copy of paternal UBE3A, which is intact but silenced by a nuclear-localized long non-coding RNA, UBE3A antisense transcript (UBE3A-ATS). Murine Ube3a-ATS reduction by either transcription termination or topoisomerase I inhibition has been shown to increase paternal Ube3a expression. Despite a clear understanding of the disease-causing event in Angelman syndrome and the potential to harness the intact paternal allele to correct the disease, no gene-specific treatment exists for patients. Here we developed a potential therapeutic intervention for Angelman syndrome by reducing Ube3a-ATS with antisense oligonucleotides (ASOs). ASO treatment achieved specific reduction of Ube3a-ATS 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. Although additional studies of phenotypic correction are needed, we have developed a sequence-specific and clinically feasible method to activate expression of the paternal Ube3a allele.
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PMID:Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. 2551

Angelman syndrome (AS) is a debilitating neurodevelopmental disorder that is characterized by motor dysfunction, intellectual disability, speech impairment, seizures and common features of autism spectrum disorders (ASDs). Some of these AS related phenotypes can be seen in other neurodevelopmental disorders (Williams, 2011; Tan et al., 2014). AS patients commonly carry mutations that render the maternally inherited UBE3A gene non-functional. Duplication of the chromosomal region containing the UBE3A gene is associated with ASDs. Although the causative role for UBE3A gene mutations in AS is well established, a long-standing challenge in AS research has been to identify neural substrates of UBE3A, an E3 ubiquitin ligase. A prevailing hypothesis is that changes in UBE3A protein levels would alter the levels of a collection of protein substrates, giving rise to the unique phenotypic aspects of AS and possibly UBE3A associated ASDs. Interestingly, proteins altered in AS are linked to additional ASDs that are not previously associated with changes in UBE3A, indicating a possible molecular overlap underlying the broad-spectrum phenotypes of these neurogenetic disorders. This idea raises the possibility that there may exist a "one-size-fits-all" approach to the treatment of neurogenetic disorders with phenotypes overlapping AS. Furthermore, while a comprehensive list of UBE3A substrates and downstream affected pathways should be developed, this is only part of the story. The timing of when UBE3A protein functions, through either changes in UBE3A or possibly substrate expression patterns, appears to be critical for AS phenotype development. These data call for further investigation of UBE3A substrates and their timing of action relevant to AS phenotypes.
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PMID:From UBE3A to Angelman syndrome: a substrate perspective. 2644 97

Deletions and reciprocal triplications of the human chromosomal 15q11-13 region cause two distinct neurodevelopmental disorders. Maternally-derived deletions or inactivating mutations of UBE3A, a 15q11-13 gene expressed exclusively from the maternal allele in neurons, cause Angelman syndrome, characterized by intellectual disability, motor deficits, seizures, and a characteristic increased social smiling, laughing, and eye contact. Conversely, maternally-derived triplications of 15q11-13 cause a behavioral disorder on the autism spectrum with clinical features that include decreased sociability that we recently reconstituted in mice with Ube3a alone. Based on the unique sociability features reported in Angelman syndrome and the repressed sociability observed when Ube3a gene dosage is increased, we hypothesized that mice with neuronal UBE3A loss that models Angelman syndrome would display evidence of hypersocial behavior. We report that mice with maternally-inherited Ube3a gene deletion (Ube3amKO) have a prolonged preference for, and interaction with, social stimuli in the three chamber social approach task. By contrast, interactions with a novel object are reduced. Further, ultrasonic vocalizations and physical contacts are increased in male and female Ube3amKO mice paired with an unfamiliar genotype-matched female. Single housing wild type mice increased these same social behavior parameters to levels observed in Ube3amKO mice where this effect was partially occluded. These results indicate sociability is repressed by social experience and the endogenous levels of UBE3A protein and suggest some social behavioral features observed in Angelman syndrome may reflect an increased social motivation.
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PMID:Hypersociability in the Angelman syndrome mouse model. 2841 Nov 25

Angelman syndrome (AS) is a neurodevelopmental disorder with leading symptoms of happy demeanor, intellectual disability, ataxia and seizures. AS can be caused by genetic and epigenetic aberrations, resulting in the absence of functional UBE3A protein in the brain. UBE3A is an imprinted gene, which is, in neurons of the brain, expressed exclusively from maternal chromosome 15. The generated iPSC line was derived from skin fibroblasts of a patient with AS, who, due to an imprinting defect, lacked DNA methylation at the chromosome 15 imprinting center, which controls maternal-specific expression of UBE3A. Resource table.
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PMID:Generation of an iPSC line of a patient with Angelman syndrome due to an imprinting defect. 3029 70

Angelman syndrome (AS) is a genetic disorder which entails autism, intellectual disability, lack of speech, motor deficits, and seizure susceptibility. It is caused by the lack of UBE3A protein expression, which is an E3-ubiquitin ligase. Despite AS equal prevalence in males and females, not much data on how sex affects the syndrome was reported. In the herein study, we thoroughly characterized many behavioral phenotypes of AS mice. The behavioral data acquired was analyzed with respect to sex. In addition, we generated a new mRNA sequencing dataset. We analyzed the coding transcriptome expression profiles with respect to the effects of genotype and sex observed in the behavioral phenotypes. We identified several neurobehavioral aspects, especially sensory perception, where AS mice either lack the male-to-female differences observed in wild-type littermates or even show opposed differences. However, motor phenotypes did not show male-to-female variation between wild-type (WT) and AS mice. In addition, by utilizing the mRNA sequencing, we identified genes and isoforms with expression profiles that mirror the sensory perception results. These genes are differentially regulated in the two sexes with inverse expression profiles in AS mice compared to WT littermates. Some of these are known pain-related and estrogen-dependent genes. The observed differences in sex-dependent neurobehavioral phenotypes and the differential transcriptome expression profiles in AS mice strengthen the evidence for molecular cross talk between Ube3a protein and sex hormone receptors or their elicited pathways. These interactions are essential for understanding Ube3a deletion effects, beyond its E3-ligase activity.
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PMID:Sex-Dependent Sensory Phenotypes and Related Transcriptomic Expression Profiles Are Differentially Affected by Angelman Syndrome. 3070 69