Glessner, J. T., Wang, K., Cai, G., Korvatska, O., Kim, C. E., Wood, S. et al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459, 569-573

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Nature (Impact Factor: 41.46). 05/2009; 459(7246):569-73. DOI: 10.1038/nature07953
Source: PubMed


Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with approximately 550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 x 10(-3)). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 x 10(-3)). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 x 10(-6)). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

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Available from: Hilary Coon, Oct 06, 2015
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    • "ASD are highly genetically determined, but the genetic factors involved in these disorders are extremely heterogeneous and have proven difficult to identify (Betancur 2011; Huguet et al. 2013; Jeste and Geschwind 2014), and, in spite of the acceleration of gene identification due to technological advances, a genetic cause is still found in a minority of ASD cases. De novo or inherited copy number variants (CNV), strongly associated with autism and probably conferring high susceptibility to ASD, have been identified in 2–10 % of patients (Girirajan et al. 2013; Sanders et al. 2011; Glessner et al. 2009; Bucan et al. 2009; Pinto et al. 2010; Huguet et al. 2013). Additional copies of the 15q11–q13 region or an abnormal number of copies in the 16p11.2 "
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    ABSTRACT: Cationic amino acid transporters (CATs) mediate the entry of L-type cationic amino acids (arginine, ornithine and lysine) into the cells including neurons. CAT-3, encoded by the SLC7A3 gene on chromosome X, is one of the three CATs present in the human genome, with selective expression in brain. SLC7A3 is highly intolerant to variation in humans, as attested by the low frequency of deleterious variants in available databases, but the impact on variants in this gene in humans remains undefined. In this study, we identified a missense variant in SLC7A3, encoding the CAT-3 cationic amino acid transporter, on chromosome X by exome sequencing in two brothers with autism spectrum disorder (ASD). We then sequenced the SLC7A3 coding sequence in 148 male patients with ASD and identified three additional rare missense variants in unrelated patients. Functional analyses of the mutant transporters showed that two of the four identified variants cause severe or moderate loss of CAT-3 function due to altered protein stability or abnormal trafficking to the plasma membrane. The patient with the most deleterious SLC7A3 variant had high-functioning autism and epilepsy, and also carries a de novo 16p11.2 duplication possibly contributing to his phenotype. This study shows that rare hypomorphic variants of SLC7A3 exist in male individuals and suggest that SLC7A3 variants possibly contribute to the etiology of ASD in male subjects in association with other genetic factors.
    Amino Acids 07/2015; DOI:10.1007/s00726-015-2057-3 · 3.29 Impact Factor
    • "Mutations within neuroligin-1 have also been found. Glessner et al. (2009) found a duplication of CNVs within NLGN1 in autistic patients compared to controls , while Ylisaukko-oja et al. (2005) reported a mutation (rs1488545) within a Finnish autistic cohort. A 6.5 year old female with development delay and a range of neurobehavioural phenotypes was found to harbor an inherited 2.1 Mb deletion (3q26.31-3q26.32) "
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    ABSTRACT: Autistic spectrum disorder (ASD) is a common, chronic psychiatric disorder for which the current generation of therapeutics are limited in their success at alleviating the neurobehaviors. While it is well established that both genetic and environmental factors contribute to the disorder, there is a lack of understanding about how ASD alters multiple domains of brain function. Identifying genes that are associated with ASD, and then relating how these genetic alterations affect brain structure and function is important to furthering our ability to design treatment and prevention strategies. Recent genome screening using copy number variant (CNV) analysis has identified deletions and duplications within the neurexin and neuroligin genes in patients with ASDs, highlighting their potential importance in ASD research. Neurexins and neuroligins are synaptic cell adhesion molecules and are found at the presynapse and postsynapse, respectively, of both excitatory and inhibitory cells. Neuroligins and leucine-rich repeat transmembranes bind to neurexins and convey a role in synaptic function and maintenance. However, little is known about how alterations within the genes encoding these proteins disrupt biological processes. Here we discuss the functional role of neurexins and neuroligins, the genetic evidence for their involvement in ASD and studies with transgenic mice to elucidate the consequences of these mutations.
    The Molecular Basis of Autism, Edited by S. Hossein Fatemi, 03/2015: chapter The Role of Neurexins and Neuroligins in Autism: pages 361-381; Springer New York., ISBN: 978-1-4939-2189-8
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    • "This puts MDGA2 in line with other neuronal cell adhesion molecules of the immunoglobulin family, such as RESEARCH ARTICLE Biology Open (2015) 000, 1–9 doi:10.1242/bio.20148482 contactins, NRCAM, CADM1 and LRFN5 that are implicated in axon migration and guidance and were associated with autism (Berglund et al., 1999; Fernandez et al., 2004; Glessner et al., 2009; Roohi et al., 2009; Cottrell et al., 2011; Morrow et al., 2008; van Daalen et al., 2011; Bonora et al., 2005; Marui et al., 2009; Zhiling et al., 2008; de Bruijn et al., 2010). In summary, the association of truncated MDGA2 variants with ASD, and the notion that a number of neuronal cell adhesion factors are implicated in ASD, supports also a role of human MDGA2 as a cell adhesion molecule important in neuronal positioning and axon guidance. "
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    ABSTRACT: The formation of functional neuronal circuits relies on accurate migration and proper axonal outgrowth of neuronal precursors. On the route to their targets migrating cells and growing axons depend on both, directional information from neurotropic cues and adhesive interactions mediated via extracellular matrix molecules or neighbouring cells. The inactivation of guidance cues or the interference with cell adhesion can cause severe defects in neuronal migration and axon guidance. In this study we have analyzed the function of the MAM domain containing glycosylphosphatidylinositol anchor 2A (MDGA2A) protein in zebrafish cranial motoneuron development. MDGA2A is prominently expressed in distinct clusters of cranial motoneurons, especially in the ones of the trigeminal and facial nerves. Analyses of MDGA2A knockdown embryos by light sheet and confocal microscopy revealed impaired migration and aberrant axonal outgrowth of these neurons; suggesting that adhesive interactions mediated by MDGA2A are required for the proper arrangement and outgrowth of cranial motoneuron subtypes. © 2015. Published by The Company of Biologists Ltd.
    Biology Open 01/2015; 4(2). DOI:10.1242/bio.20148482 · 2.42 Impact Factor
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