Novel Submicroscopic Chromosomal Abnormalities Detected in Autism Spectrum Disorder

Christian, Susan L.; Brune, Camille W.; Sudi, Jyotsna; Kumar, Revati; Liu, Shaung; Karamohamed, Samer; Badner, Judith A.; Matsui, Seiichi; Conroy, Jeffrey M.; McQuaid, Devin; Gergel, James; Hatchwell, Eli; Gilliam, T. Conrad; Gershon, Elliot S.; Nowak, Norma J.; Dobyns, William B.; Cook, Edwin H.

doi:10.1016/j.biopsych.2008.01.009

Cited by 277 publications

(250 citation statements)

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“…For example, UBE3A may act by ubiquitinating SOD1 (Superoxide dismutase 1), which can itself act as a nuclear transcription factor (Mishra et al, 2013;Tsang et al, 2014). SOD1 mutations have been linked to autism (Kovac et al, 2014), which in turn has been linked to maternal 15q11-13 copy number variation that may cause UBE3A overexpression, and to modified phosphorylation that can cause UBE3A hyperfunction (Cook et al, 1997;Christian et al, 2008;Glessner et al, 2009;Hogart et al, 2009;Hogart et al, 2010;Iossifov et al, 2014;Yi et al, 2015). UBE3A also exhibits transcriptional effects independent of its role as an E3 ligase (El Hokayem and Nawaz, 2014).…”

Section: Ube3a In the Nucleusmentioning

confidence: 99%

Subcellular organization of UBE3A in neurons

Burette

Judson

Burette

et al. 2016

J of Comparative Neurology

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Ubiquitination regulates a broad array of cellular processes, and defective ubiquitination is implicated in several neurological disorders. Loss of the E3 ubiquitin-protein ligase UBE3A causes Angelman syndrome. Despite its clinical importance, the normal role of UBE3A in neurons is still unclear. As a step toward deciphering its possible functions, we performed high-resolution light and electron microscopic immunocytochemistry. We report a broad distribution of UBE3A in neurons, highlighted by concentrations in axon terminals and euchromatin-rich nuclear domains. Our findings suggest that UBE3A may act locally to regulate individual synapses, while also mediating global, neuron-wide influences through the regulation of gene transcription. KeywordsAngelman syndrome; E6-AP; ubiquitin-proteasome pathway; axon terminal; mitochondria; euchromatin; heterochromatin; RRID:nif-0000-30467; RRID:AB_10740376The ubiquitin-proteasome pathway, which provides a mechanism for protein degradation in eukaryotes, is important for a broad array of basic cellular processes. Neurons have long dendrites and axons whose distal regions are remote from the soma, emphasizing the importance of local protein synthesis and degradation in neuronal function. Accordingly, the ubiquitin-proteasome pathways has been shown to be important for appropriate circuit wiring, neuronal morphogenesis, intracellular trafficking, and synaptic plasticity (Hegde, * Correspondence to: Benjamin D. Philpot, bphilpot@med.unc.edu, Richard J. Weinberg, richard.weinberg@gmail.com. Conflict of interest statementAuthors verify that they have no known or potential conflict of interest including any financial, personal, or other relationships with other people or organizations within 3 years of beginning the submitted work that could inappropriately influence, or be perceived to influence, this work. 2004;Acconcia et al., 2009;Cajigas et al., 2010;Schwarz and Patrick, 2012;Hamilton and Zito, 2013;Goo et al., 2015). Conversely, dysregulation of the ubiquitin-proteasome system has been implicated in multiple neurological disorders including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and autism (Tai and Schuman, 2008;Schwarz and Patrick, 2012). HHS Public AccessThe covalent attachment of ubiquitin to protein substrates involves sequential reactions catalyzed by a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein ligase (E3). The E3 ligases largely dictate specificity and target protein recognition for the ubiquitin conjugation system; thus the biology of E3 ligases is of broad biological and clinical importance. Based on their distinct domains and mode of action, E3 proteins segregate into three families: RING/RING-like E3s, RING-in-between-RING (RBR) E3s, and Homologous to the E6-AP Carboxyl Terminus (HECT) E3s. The loss of expression or function of UBE3A (also called E6-AP), the founding member of the HECT E3 ligase family, leads to Angelman syndrome (AS), a severe n...

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Section: Ube3a In the Nucleusmentioning

confidence: 99%

Subcellular organization of UBE3A in neurons

Burette

Judson

Burette

et al. 2016

J of Comparative Neurology

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“…The absence of additional cases of 2p15-p16.1 deletion in our own ASD study cohort (n¼798), and at least 2586 cases from other published studies [31][32][33][34][35] suggests that the involvement of 2p15-p16.1 with autism is a rare event. Given that the presence of dysmorphic features represents an exclusion criterion for several ASD studies, this may reduce the frequency of detection of 2p15-p16.1 deletions in other screening studies.…”

Section: Discussionmentioning

confidence: 51%

“…To determine the frequency of 2p15-p16.1 deletions among individuals with ASDs, we tested 798 individuals with an ASD for the presence of microdeletions similar to those described in Subjects 1 and 2; none were found. Furthermore, no similar cases have been reported from five other published studies, [31][32][33][34][35] with at least 3410 subjects with an ASD evaluated for CNVs. However, Liang et al 13 reported a case with the 2p15-p16.1 deletion with autism.…”

Section: Discussionmentioning

confidence: 99%

2p15–p16.1 microdeletion syndrome: molecular characterization and association of the OTX1 and XPO1 genes with autism spectrum disorders

Malenfant

Reesor

et al. 2011

Eur J Hum Genet

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Reports of unrelated individuals with autism spectrum disorder (ASD) and similar clinical features having overlapping de novo interstitial deletions at 2p15-p16.1 suggest that this region harbors a gene(s) important to the development of autism. We molecularly characterized two such deletions, selecting two genes in this region, exportin 1 (XPO1) and orthodenticle homolog 1 (OTX1) for association studies in three North American cohorts (Autism Spectrum Disorder -Canadian American Research Consortium (ASD-CARC), New York, and Autism Genetic Resource Exchange (AGRE)) and one Italian cohort (Società Italiana per la Ricerca e la Formazione sull'Autismo (SIRFA)) of families with ASD. In XPO1, rs6735330 was associated with autism in all four cohorts (Po0.05), being significant in ASD-CARC cohorts (P-value following false discovery rate correction for multiple testing (P FDR )¼1.29Â10 À5 ), the AGRE cohort (P FDR ¼0.0011) and the combined families (P FDR ¼2.34Â10 À9 ). Similarly, in OTX1, rs2018650 and rs13000344 were associated with autism in ASD-CARC cohorts (P FDR ¼8.65Â10 À7 and 6.07Â10 5 , respectively), AGRE cohort (P FDR ¼0.0034 and 0.015, respectively) and the combined families (P FDR ¼2.34Â10 À9 and 0.00017, respectively); associations were marginal or insignificant in the New York and SIRFA cohorts. A significant association (P FDR ¼2.63Â10 À11 ) was found for the rs2018650G-rs13000344C haplotype. The above three SNPs were associated with severity of social interaction and verbal communication deficits and repetitive behaviors (P-values o0.01). No additional deletions were identified following screening of 798 ASD individuals. Our results indicate that deletion 2p15-p16.1 is not commonly associated with idiopathic ASD, but represents a novel contiguous gene syndrome associated with a constellation of phenotypic features (autism, intellectual disability, craniofacial/CNS dysmorphology), and that XPO1 and OXT1 may contribute to ASD in 2p15-p16.1 deletion cases and non-deletion cases of ASD mapping to this chromosome region.

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“…Here we shall only point out that the role of CNVs is actually more complex than may appear. Initial studies suggested the existence of genomic instability in a sizable group of ASD patients, because de novo CNVs (i.e., microdeletions or microduplications present only in the patient and not in his/her parents) were significantly more common in autistic compared to healthy individuals [15][16][17]. In reality, the overall number of CNVs was later shown to be similar in ASD cases and controls, while rare CNVs overlapping coding genes are enriched in ASD cases, especially so for loci involved in synaptic and neuronal cell adhesion, ubiquitination, cell proliferation and migration, GTPase/Ras signaling [18][19][20].…”

Section: Trends In Autism Genetic Researchmentioning

confidence: 99%