Linkage Disequilibrium at the Angelman Syndrome Gene UBE3A in Autism Families

doi:10.1006/geno.2001.6617

Genomics

Volume 77, Issues 1–2, September 2001, Pages 105-113

https://doi.org/10.1006/geno.2001.6617 Get rights and content

Abstract

Autistic disorder is a neurodevelopmental disorder with a complex genetic etiology. Observations of maternal duplications affecting chromosome 15q11–q13 in patients with autism and evidence for linkage and linkage disequilibrium to markers in this region in chromosomally normal autism families indicate the existence of a susceptibility locus. We have screened the families of the Collaborative Linkage Study of Autism for several markers spanning a candidate region covering ∼2 Mb and including the Angelman syndrome gene (UBE3A) and a cluster of γ-aminobutyric acid (GABA_A) receptor subunit genes (GABRB3, GABRA5, and GABRG3). We found significant evidence for linkage disequilibrium at marker D15S122, located at the 5′ end of UBE3A. This is the first report, to our knowledge, of linkage disequilibrium at UBE3A in autism families. Characterization of null alleles detected at D15S822 in the course of genetic studies of this region showed a small (∼5-kb) genomic deletion, which was present at somewhat higher frequencies in autism families than in controls.

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Developmental disabilities, autism, and schizophrenia at a single locus: complex gene regulation and genomic instability of 15q11-q13 cause a range of neurodevelopmental disorders
2020, Neurodevelopmental Disorders: Comprehensive Developmental Neuroscience
The chromosome 15q11-q13 locus is a highly unstable genomic region prone to recurrent duplications and deletions and governed by complex gene regulation mechanisms that include imprinting, chromatin conformational changes, and antisense regulatory transcripts. As a consequence of this complexity, the genes in the 15q region are frequently subjected to dramatic changes in dosage and tissue-specific expression resulting in a spectrum of neurodevelopmental disorders including Angelman syndrome, Prader–Willi syndrome, Schaaf-Yang syndrome, duplication 15q syndrome, and schizophrenia. Here we provide an overview of our current knowledge of gene function and regulation in this region, describe the primary neurodevelopmental syndromes associated with 15q, describe current animal models of these disorders, and touch on new therapeutic approaches to one of these neurogenetic syndromes.
Genetic variation of UBE3A is associated with schizotypy in a population of typical individuals
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Citation Excerpt :
A later study by the same group, using six intronic SNP markers within UBE3A did not find any significant pattern of preferential transmission in autism families (Nurmi et al., 2003). Guffanti et al. (2011) found that an allele of the microsatellite marker D15S122 showed preferential under transmission to affected children, partially replicating the earlier results of Nurmi et al. (2001). Here, the microsatellite marker was analyzed as four classes of different alleles designated as 222-bp, 224-bp, 226-bp and other lengths, with the three main alleles covering the majority of the variation.
The maternally expressed imprinted gene UBE3A has been implicated in autism, schizophrenia and psychosis. The phenotype of Angelman syndrome, caused by loss of UBE3A expression, involves autism spectrum traits, while Prader-Willi syndrome, where the genotype of maternal disomy increases dosage of UBE3A, shows high penetrance for the development of psychosis. Maternal duplications of the 15q11-q13 chromosome region that overlap the imprinted region also show an association with schizophrenia, further implying a connection between increased dosage of UBE3A and the development of schizophrenia and psychosis. We phenotyped a large population of typical individuals for autism spectrum and schizotypal traits and genotyped them for a set of SNPs in UBE3A. Genetic variation of rs732739, an intronic SNP tagging a large haplotype spanning nearly the entire range of UBE3A, was significantly associated with variation in total schizotypy. Our results provide an independent line of evidence, connecting the imprinted UBE3A gene to the schizophrenia spectrum.
Network Analysis of UBE3A/E6AP-Associated Proteins Provides Connections to Several Distinct Cellular Processes
2018, Journal of Molecular Biology
Citation Excerpt :
In addition, UBE3A is linked to two different neurological disorders. Increased gene dosage of UBE3A is implicated in some forms of autism spectrum disorders (ASDs) [8–10], and the loss of function of UBE3A in the central nervous system is the cause of Angelman syndrome (AS), a neurodevelopmental disorder characterized by severe mental retardation, ataxia, loss of speech, seizures, and other abnormalities [11–14]. Approximately 10% of patients that meet the clinical criteria for AS have no identified UBE3A molecular defect [15], suggesting that in addition to molecular mechanisms directly affecting UBE3A, perturbations in other genes that share a pathway or work through convergent pathways with UBE3A may also cause AS.
Perturbations in activity and dosage of the UBE3A ubiquitin-ligase have been linked to Angelman syndrome and autism spectrum disorders. UBE3A was initially identified as the cellular protein hijacked by the human papillomavirus E6 protein to mediate the ubiquitylation of p53, a function critical to the oncogenic potential of these viruses. Although a number of substrates have been identified, the normal cellular functions and pathways affected by UBE3A are largely unknown. Previously, we showed that UBE3A associates with HERC2, NEURL4, and MAPK6/ERK3 in a high-molecular-weight complex of unknown function that we refer to as the HUN complex (HERC2, UBE3A, and NEURL4). In this study, the combination of two complementary proteomic approaches with a rigorous network analysis revealed cellular functions and pathways in which UBE3A and the HUN complex are involved. In addition to finding new UBE3A-associated proteins, such as MCM6, SUGT1, EIF3C, and ASPP2, network analysis revealed that UBE3A-associated proteins are connected to several fundamental cellular processes including translation, DNA replication, intracellular trafficking, and centrosome regulation. Our analysis suggests that UBE3A could be involved in the control and/or integration of these cellular processes, in some cases as a component of the HUN complex, and also provides evidence for crosstalk between the HUN complex and CAMKII interaction networks. This study contributes to a deeper understanding of the cellular functions of UBE3A and its potential role in pathways that may be affected in Angelman syndrome, UBE3A-associated autism spectrum disorders, and human papillomavirus-associated cancers.
Autism spectrum disorders: Integration of the genome, transcriptome and the environment
2016, Journal of the Neurological Sciences
Autism spectrum disorders denote a series of lifelong neurodevelopmental conditions characterized by an impaired social communication profile and often repetitive, stereotyped behavior. Recent years have seen the complex genetic architecture of the disease being progressively unraveled with advancements in gene finding technology and next generation sequencing methods. However, a complete elucidation of the molecular mechanisms behind autism is necessary for potential diagnostic and therapeutic applications. A multidisciplinary approach should be adopted where the focus is not only on the ‘genetics’ of autism but also on the combinational roles of epigenetics, transcriptomics, immune system disruption and environmental factors that could all influence the etiopathogenesis of the disease. ASD is a clinically heterogeneous disorder with great genetic complexity; only through an integrated multidimensional effort can modern autism research progress further.
Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops
2016, Neuron
Understanding the mechanisms underlying autism spectrum disorders (ASDs) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry, and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops and provide detailed commentary for exemplar genes within each module.
A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology
2015, American Journal of Human Genetics
The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

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Regular ArticleLinkage Disequilibrium at the Angelman Syndrome Gene UBE3A in Autism Families

Abstract

Trends Genet.

Am. J. Hum. Genet.

Genet. Med.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Genomics

Genomics

J. Biol. Chem.

Genomics

Am. J. Hum. Genet.

Am. J. Hum. Genet.

Autism: the phenotype in relatives

J. Autism Dev. Disord.

The epidemiology of autism: a review

Psychol. Med.

Autism: the point of view from fragile X studies

J. Autism Dev. Disord.

Autism

N. Engl. J. Med.

Autism and tuberous sclerosis

J. Autism Dev. Disord.

Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism

Am. J. Hum. Genet.

Autism as a strongly genetic disorder: evidence from a British twin study

Psychol. Med.

Genetics and child psychiatry: II Empirical research findings

J. Child. Psychol. Psychiatry

Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons

Nat. Genet.

The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain

Nat. Genet.

Regular Article
Linkage Disequilibrium at the Angelman Syndrome Gene UBE3A in Autism Families