Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

Division of Genetics, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Science (Impact Factor: 33.61). 08/2008; 321(5886):218-23. DOI: 10.1126/science.1157657
Source: PubMed


To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the
role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely
mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that
underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of “homozygosity
mapping” in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural
activity may be a mechanism common to seemingly diverse autism mutations.


Available from: Nahit Motavalli Mukaddes
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    • "Member of the GADD45 family associated with DNA damage repair and DNA demethylation; other members of GADD45 family (GADD45a and GADD45b) are involved in neurite outgrowth and activity-induced DNA demethylation (e.g., Bdnf and Fgf; [40, 63]); activated in human epileptic neocortex [75] Autism, intellectual disability 270400 Acan Component of perineuronal nets around parvalbumin interneurons; disruption of perineuronal nets leads to seizure-like activity in hippocampal cultures [72]; loss of aggrecan staining is observed after status epilepticus (1–2 weeks; [31]) Intellectual disability 261718 Lcn2 Small, inducible, secreted protein, identified as a protein associated with matrix metalloproteinase-9 [42]; Lcn2 KO animals show increased spine density and neuronal excitability in hippocampus and amygdala [64, 74] Autism, severe intellectual disability 289308 Pcdh8 Upregulated in response to neuronal activity or seizures; required for induction of long-term potentiation [43]; regulates dendritic spine number [65]; other members of Pcdhs family (Pcdh10 and Pcdh19) are associated with neuropsychiatric disorders (epilepsy, mental retardation, autism-spectrum disorders; [44, 45] Intellectual disability 260940 Elmo1 Regulates actin cytoskeleton reorganization; localized to excitatory synapses and is required for spine formation in hippocampal neurons [66] Autism, severe intellectual disability 289704 Magoh Core protein of the exon junction complex that regulates metabolism of spliced mRNA; targets mRNA for nonsense-mediated decay; controls brain size by regulating neural stem cell division [46]; lack of another exon junction complex component, eIF4A3, increases synaptic strength and GLUR1 AMPA receptor abundance at synapses and increases Arc protein levels [47] Intellectual disability 272313 Zfp36 RNA-binding protein; interacts with AU-rich sequences in the 3′ untranslated region of targeted mRNAs and promotes their degradation; activated in human epileptic neocortex [75] Global developmental delay 277936 "
    [Show abstract] [Hide abstract] ABSTRACT: Although the transcription factor serum response factor (SRF) has been suggested to play a role in activity-dependent gene expression and mediate plasticity-associated structural changes in the hippocampus, no unequivocal evidence has been provided for its role in brain pathology, such as epilepsy. A genome-wide program of activity-induced genes that are regulated by SRF also remains unknown. In the present study, we show that the inducible and conditional deletion of SRF in the adult mouse hippocampus increases the epileptic phenotype in the kainic acid model of epilepsy, reflected by more severe and frequent seizures. Moreover, we observe a robust decrease in activity-induced gene transcription in SRF knockout mice. We characterize the genetic program controlled by SRF in neurons and using functional annotation, we find that SRF target genes are associated with synaptic plasticity and epilepsy. Several of these SRF targets function as regulators of inhibitory or excitatory balance and the structural plasticity of neurons. Interestingly, mutations in those SRF targets have found to be associated with such human neuropsychiatric disorders, as autism and intellectual disability. We also identify novel direct SRF targets in hippocampus: Npas4, Gadd45g, and Zfp36. Altogether, our data indicate that proteins that are highly upregulated by neuronal stimulation, identified in the present study as SRF targets, may function as endogenous protectors against overactivation. Thus, the lack of these effector proteins in SRF knockout animals may lead to uncontrolled excitation and eventually epilepsy.
    Full-text · Article · Jan 2015 · Molecular Neurobiology
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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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jan 2015 · Biology Open
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    • "High-resolution molecular karyotyping is a powerful tool to identify a large number of DNA gains and losses that are associated with various neurological phenotypes, but the yield is typically <15%, and it rarely identifies single genes due to the nature of the assay (Miller et al., 2010). Morrow et al. used autozygosity mapping in nearly 90 consanguineous families with autism, followed by Sanger sequencing of candidate genes within the linked ROH, to identify five novel autism genes (Morrow et al., 2008). The lower yield of that study likely originates from the use of conventional sequencing methods, coupled with the potentially non-Mendelian behavior of autism genes. "
    [Show abstract] [Hide abstract] ABSTRACT: Neurogenetic disorders represent the largest category of Mendelian diseases in humans. They encompass a wide array of clinical presentations that range from the common e.g., intellectual disability (>1%) to the very rare, e.g., neurodegeneration with brain iron accumulation (one to three per 106) (Kalman et al., 2012 and Maulik et al., 2011). The highly prevalent involvement of the nervous system in many Mendelian disorders coincides with the observation that >80% of all human genes are expressed at some stage of brain development (Hawrylycz et al., 2012) and suggests that the brain is one of the most vulnerable organs to genetic perturbation. In fact high-resolution microarray analysis of the human genome reveals that intellectual disability is the common phenotypic denominator of genomic disorders that involve losses or gains of genes (Coe et al., 2012).
    Full-text · Article · Dec 2014 · Cell Reports
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