Turner Tychele N, Sharma Kamal, Oh Edwin C, Liu Yangfan P, Collins Ryan L, Sosa Maria X, Auer Dallas R, Brand Harrison, Sanders Stephan J, Moreno-De-Luca Daniel, Pihur Vasyl, Plona Teri, Pike Kristen, Soppet Daniel R, Smith Michael W, Cheung Sau Wai, Martin Christa Lese, State Matthew W, Talkowski Michael E, Cook Edwin, Huganir Richard, Katsanis Nicholas, Chakravarti Aravinda
1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nature. 2015 Apr 2;520(7545):51-6. doi: 10.1038/nature14186. Epub 2015 Mar 25.
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.
自闭症是一种多因素神经发育障碍，男性患者多于女性；因此，在多因素遗传假说下，女性只有在跨越更高的生物学阈值时才会受到影响。我们假设，在来自女性富集的严重疾病多重家庭的严重受影响患者中，保守残基处的有害变异会富集，从而在少量病例中增强对关键自闭症基因的检测。在此，我们展示了该策略的应用，即在女性富集的多重家庭中鉴定编码与黏附连接相关的δ-连环蛋白（CTNND2）的基因中的错义及剂量序列变异，并通过对斑马鱼胚胎以及野生型和Ctnnd2基因敲除小鼠胚胎的培养海马神经元进行功能分析，证明这些变异的功能丧失效应。最后，通过基因表达和网络分析，我们强调了CTNND2在神经元发育中的关键作用以及与染色质生物学的紧密联系。我们的数据有助于理解自闭症的遗传结构，并表明对表型极端情况（如女性富集的多重家庭）进行遗传分析在多因素疾病中具有内在价值。
