Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number

Judson

J of Comparative Neurology

et al. 2016

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...

Section: Ube3a In the Nucleusmentioning

confidence: 99%

Subcellular organization of UBE3A in neurons

Judson

J of Comparative Neurology

et al. 2016

“…4 Maternal duplications of this region are the most commonly identified genetic cause of autism, 5 with prevalence estimates in autism ranging from 0.5% to 3%. 3 Multiple genes from this region are implicated in the pathogenesis of autism spectrum disorders, epilepsy, and schizophrenia, 2,[6][7][8] and numerous studies implicate UBE3A as the causative gene resulting in impaired cognitive function in AS. 9 These results suggest that altered function of UBE3A through underexpression (AS) or overexpression (idic (15) or int dup (15)) impairs neurocognitive development.…”

mentioning

confidence: 99%

A survey of seizures and current treatments in 15q duplication syndrome

et al. 2014

SUMMARYObjective: Seizures are common in individuals with duplications of chromosome 15q11.2-q13 (Dup15q). The goal of this study was to examine the phenotypes and treatments of seizures in Dup15q in a large population. Methods: A detailed electronic survey was conducted through the Dup15q Alliance containing comprehensive questions regarding seizures and their treatments in Dup15q.Results: There were 95 responses from Dup15q families. For the 83 with idic(15), 63% were reported to have seizures, of which 81% had multiple seizure types and 42% had infantile spasms. Other common seizure types were tonic-clonic, atonic, myoclonic, and focal. Only 3 of 12 individuals with int dup(15) had seizures. Broad spectrum antiepileptic drugs (AEDs) were the most effective medications, but carbamazepine and oxcarbazepine were also effective, although typical benzodiazepines were relatively ineffective. There was a 24% response rate (>90% seizure reduction) to the first AED tried. For those with infantile spasms, adrenocorticotropic hormone (ACTH) was more effective than vigabatrin. Significance: This is the largest study assessing seizures in Duplication 15q syndrome, but because this was a questionnaire-based study with a low return rate, it is susceptible to bias. Seizures are common in idic(15) and typically difficult to control, often presenting with infantile spasms and progressing to a Lennox-Gastaut-type syndrome. Seizures in those with int dup(15) are less common, with a frequency similar to the general autism population. In addition to broad spectrum AED, medications such as carbamazepine and oxcarbazepine are also relatively effective in controlling seizures in this population, suggesting a possible multifocal etiology, which may also explain the high rate of infantile spasms. Our small sample suggests a relative lack of efficacy of vigabatrin and other c-aminobutyric acid (GABA)ergic medications, such as typical benzodiazepines, which may be attributable to abnormal GABAergic transmission resulting from the duplication of a cluster of GABAb3 receptor genes in the 15q11.2-13 region.

“…This can disrupt normal parental homologue pairing, DNA methylation patterns, and gene expression patterns within 15q11-13. Features of autism, along with cognitive impairment, anxiety, and hyperactivity are seen in 15q duplication syndrome [45][46][47][48][49][50]. Penetrance of the autism phenotype is complete in patients with idic15.…”

Section: Duplication Of Chromosome 15q11-13mentioning

confidence: 91%

Epigenetics, Autism Spectrum, and Neurodevelopmental Disorders

2013

Epigenetic marks are modifications of DNA and histones. They are considered to be permanent within a single cell during development, and are heritable across cell division. Programming of neurons through epigenetic mechanisms is believed to be critical in neural development. Disruption or alteration in this process causes an array of neurodevelopmental disorders, including autism spectrum disorders (ASDs). Recent studies have provided evidence for an altered epigenetic landscape in ASDs and demonstrated the central role of epigenetic mechanisms in their pathogenesis. Many of the genes linked to the ASDs encode proteins that are involved in transcriptional regulation and chromatin remodeling. In this review we highlight selected neurodevelopmental disorders in which epigenetic dysregulation plays an important role. These include Rett syndrome, fragile X syndrome, Prader-Willi syndrome, Angelman syndrome, and Kabuki syndrome. For each of these disorders, we discuss how advances in our understanding of epigenetic mechanisms may lead to novel therapeutic approaches.