Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

Disabled 1 (DAB1) 是 Reelin 信号通路中的一种细胞内衔接蛋白，在发育中的大脑中正确的神经元迁移和层形成中发挥着重要作用。在遗传、动物和尸检研究中， DAB1被多次报道与神经发育障碍有关，包括精神分裂症 (SCZ) 和自闭症谱系障碍 (ASD)。最近，通过候选基因深度测序发现的罕见单核苷酸变异（SNV）受到越来越多的关注。在这项研究中，我们使用下一代测序技术对 370 名 SCZ 和 192 名 ASD 患者进行了DAB1外显子靶向重测序，以鉴定具有次要等位基因频率 <1% 的罕见 SNV。我们检测到两种罕见的错义突变（G382C、V129I），然后在包含 1763 名 SCZ、380 名 ASD 和 2190 名健康对照受试者的样本中进行了遗传关联研究。尽管在 SCZ 或 ASD 中未观察到与检测到的突变有统计学上的显着关联，但仅在病例组中发现了 G382C，并且计算机分析和体外功能测定表明 G382C 改变了 DAB1 蛋白的功能。本研究中发现的DAB1罕见变异应进一步研究，以阐明它们与 SCZ 和 ASD 病理生理学的潜在功能相关性。