Genetic and Functional Analyses of SHANK2 Mutations Suggest a Multiple Hit Model of Autism Spectrum Disorders

Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.
PLoS Genetics (Impact Factor: 7.53). 02/2012; 8(2):e1002521. DOI: 10.1371/journal.pgen.1002521
Source: PubMed


Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Download full-text


Available from: Martin Poot
  • Source
    • "Abbreviations: ADHD, attention-deficit hyperactivity disorder; ASD, autism spectrum disorder; FMR1, fragile X mental retardation ; FXS, fragile X syndrome; PON1, paraoxanase/arylesterase 1; PPI, protein–protein interaction; SLOS, Smith-Lemli-Opitz syn- drome ASD is likely a heterogeneous disorder with multiple causes, involving genes and the environment [8] [9] [10]. Numerous genetic studies of ASD have been conducted [11], supporting not only a strong genetic link in many cases, but also a high likely degree of heterogeneity of cause [12]. Many implicated genes are involved in nervous system development and neurotransmitter systems [13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Current directions in autism spectrum disorder (ASD) research may require moving beyond genetic analysis alone, based on the complexity of the disorder, heterogeneity and convergence of genetic alterations at the cellular/functional level. Mass spectrometry (MS) has been increasingly used to study central nervous system (CNS) disorders, including ASDs. Proteomic research using MS is directed at understanding endogenous protein changes that occur in ASD. This review focuses on how MS has been used to study ASDs, with particular focus on proteomic analysis. Other neurodevelopmental disorders have been investigated using MS, including fragile X syndrome (FXS) and Smith-Lemli-Opitz Syndrome (SLOS), genetic syndromes highly associated with ASD comorbidity.This article is protected by copyright. All rights reserved
    Full-text · Article · Feb 2015 · PROTEOMICS - CLINICAL APPLICATIONS
  • Source
    • "Since involvement of CNTN5 in ASD has been supported by both the CNV and the present candidate gene association study, further neurobiological and, in particular, neurobehavioral studies of this gene appear warranted [Poot, 2013]. It is conceivable that CNTN5 , in analogy to recently reported findings with SHANK2 in patients with ASD and ID [Leblond et al., 2012; Chilian et al., 2013], may be part of a gene interaction network consisting of physical interactions between the encoded proteins [Poot et al., 2011]. Alternatively, genes may form a network of epistatic regulation consisting of transcription factors and their cognate target sites. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although autism spectrum disorder (ASD) shows a high degree of heritability, only a few mutated genes and mostly de novo copy number variations (CNVs) with a high phenotypic impact have as yet been identified. In families with multiple ASD patients, transmitted CNVs often do not appear to cosegregate with disease. Therefore, also transmitted single nucleotide variants which escape detection if genetic analyses were limited to CNVs may contribute to disease risk. In several studies of ASD patients, CNVs covering at least one gene of the contactin gene family were found. To determine whether there is evidence for a contribution of transmitted variants in contactin genes, a cohort of 67 ASD patients and a population-based reference of 117 healthy individuals, who were not related to the ASD families, were compared. In total, 1,648 SNPs, spanning 12.1 Mb of genomic DNA, were examined. After Bonferroni correction for multiple testing, the strongest signal was found for a SNP located within the CNTN5 gene (rs6590473 [G], p = 4.09 × 10(-7); OR = 3.117; 95% CI = 1.603-6.151). In the ASD cohort, a combination of risk alleles of SNPs in CNTN6 (rs9878022 [A]; OR = 3.749) and in CNTNAP2 (rs7804520 [G]; OR = 2.437) was found more frequently than would be expected under random segregation, albeit this association was not statistically significant. The latter finding is consistent with a polygenic disease model in which multiple mutagenic mechanisms, operating concomitantly, elicit the ASD phenotype. Altogether, this study corroborates the possible involvement of contactins in ASD, which has been indicated by earlier studies of CNVs.
    Full-text · Article · Aug 2014 · Molecular syndromology
  • Source
    • "Some studies even question the possibility of any substantial impact of monogenic forms of ASD [97]. ASD is known to be a complex multifactorial disease [95-98,123] although several rare single-gene disorders with a high prevalence of ASD are known [38,113]. We speculate that the impact of synonymous variations/mutations is small but sufficient to produce phenotypic effects in synergy with the increasing neurotoxin load. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BackgroundA dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage.Presentation of the hypothesisWe hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins.Testing the hypothesisA statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models.Implications of the hypothesisIt seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence.ReviewersThis article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.
    Full-text · Article · Jul 2014 · Biology Direct
Show more