The Comorbidity of Autism with the Genomic Disorders of Chromosome 15q11.2-q13

Department of Medical Microbiology and Immunology, University of California, Davis, CA 95616, USA.
Neurobiology of Disease (Impact Factor: 5.08). 10/2008; 38(2):181-91. DOI: 10.1016/j.nbd.2008.08.011
Source: PubMed


A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.

Download full-text


Available from: Janine M Lasalle, Dec 17, 2013
1 Follower
51 Reads
  • Source
    • "Duplication or triplication of maternally inherited 15q11-13, the chromosomal location where UBE3A resides, is one of the most common cytogenetic events associated with autism (Glessner et al., 2009; Hogart et al., 2010). Individuals with one extra maternal copy of 15q11-13 display partial autism penetrance, whereas individuals with two extra copies display almost complete penetrance (Hogart et al., 2010; Urraca et al., 2013). UBE3A is the only gene in this region that is consistently expressed from the maternal, but not paternal, allele in mature neurons (Albrecht et al., 1997; Rougeulle et al., 1997; Vu and Hoffman, 1997), suggesting that abnormally elevated levels of UBE3A contribute to autism in 15q11-13 duplication syndrome. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS), while duplication or triplication of UBE3A is linked to autism. These genetic findings suggest that the ubiquitin ligase activity of UBE3A must be tightly maintained to promote normal brain development. Here, we found that protein kinase A (PKA) phosphorylates UBE3A in a region outside of the catalytic domain at residue T485 and inhibits UBE3A activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient-derived cells, and excessive dendritic spine development in the brain. Our study identifies PKA as an upstream regulator of UBE3A activity and shows that an autism-linked mutation disrupts this phosphorylation control. Moreover, our findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 08/2015; 162(4). DOI:10.1016/j.cell.2015.06.045 · 32.24 Impact Factor
  • Source
    • "Various studies have linked ASD with the maternally but not paternally derived duplication of the PWS 15q11–13 critical region with duplications of the 15q11–13 region occurring in 3–5 % of cases with idiopathic autism (Hogart et al. 2010; Veltman et al. 2004). Based on these findings, it is evident that the mUPD subtype of PWS shares a genetic similarity with ASD, in that both may show increased maternal expression of the 15q11–13 region (Hogart et al. 2010; Veltman et al. 2004). In relation to this genetic similarity, current research has found that individuals with PWS, and the mUPD subtype, have an increased risk for developing autistic-like symptoms and express similar patterns of repetitive behaviors and social competency deficits as those with ASD (Descheemaeker et al. 2006; Dimitropoulos et al. 2012; Dykens et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Children with Prader-Willi syndrome (PWS) are at risk for autism spectrum disorder (ASD), including pervasive social deficits. While play impairments in ASD are well documented, play abilities in PWS have not been evaluated. Fourteen children with PWS and ten children with ASD were administered the Autism Diagnostic Observation Schedule (ADOS) (Lord et al. in Autism Diagnostic Observation Schedule manual. Western Psychological Services, Los Angeles, 2006) as part of a larger project. A modified Affect in Play Scale (APS; Russ in Play in child development and psychotherapy: toward empirically supported practice. Lawrence Erlbaum Associates Publishers, Mahwah, 2004; Pretend play in childhood: foundation of adult creativity. APA Books, Washington, 2014) was used to score ADOS play activities. Results indicate both groups scored below normative data on measures of imagination, organization, and affective expression during individual play. In addition, the inclusion of a play partner in both groups increased all scaled scores on the APS. These findings suggest children with PWS show impaired pretend play abilities similar to ASD. Further research is warranted and should focus on constructing and validating programs aimed at improving symbolic and functional play abilities within these populations.
    Journal of Autism and Developmental Disorders 09/2014; 45(4). DOI:10.1007/s10803-014-2252-1 · 3.34 Impact Factor
  • Source
    • "Also, the behavior of some patients with PWS gradually comes to resemble that of an autism spectrum disorder (ASD) [Veltman et al., 2005]. In this respect, it has been suggested that the maternal duplications of 15q11–13 have an association with autistic spectrum disorders (ASD) [Bolton et al., 2001; Veltman et al., 2005; Dimitropoulos and Schultz, 2007; Hogart et al., 2010]. Furthermore, there is a growing tendency for autistic behavioral problems, which are more severe in mUPD than in DEL, to manifest themselves later in adolescence [Ihara et al., 2013]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This study aimed to measure quality of life (QOL) of the primary family caregivers for patients with Prader-Willi syndrome (PWS). Comparisons were made between caregivers' QOL in regard to their dependents' genotype and age group. The participants with PWS consisted of 22 children (aged from 6 to 12 years) and 23 adolescents (aged from 13 to 19 years), including 6 children and 7 adolescents with maternal uniparental disomy (mUPD) and 16 children and 16 adolescents with deletion (DEL). The QOL of the primary family caregiver for each patient was assessed using the Japanese version of the WHOQOL-BREF. To examine the effect that age (children vs. adolescents) and genotype (DEL vs. mUPD) have on the QOL of caregivers, a two-way ANOVA was conducted, followed by the Bonferroni procedure to test the simple main effects. The two age groups and the two genotypes of PWS were used as independent variables and the total QOL of caregivers as a dependent variable. The two-way ANOVA (F(1, 41) = 6.98, P < 0.05), followed by the Bonferroni procedure, showed the following: the total QOL of caregivers of DEL adolescents showed little difference from that with DEL children, but the QOL of caregivers for mUPD adolescents was shown to be lower than that with mUPD children along with that of caregivers with DEL adolescents. There is hence a growing tendency for the deterioration in the QOL of caregivers to manifest itself later in the patients' adolescence, found mainly with mUPD patients. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2014; 164A(9). DOI:10.1002/ajmg.a.36634 · 2.16 Impact Factor
Show more