PDF(Pubmed)
Abstract：
CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.
摘要：
CSMD1（Cub和Sushi多个域1）是公认的补体级联调节因子，先天免疫反应的重要组成部分。CSMD1在中枢神经系统（CNS）中高度表达，其中补体途径的新兴功能调节神经发育和突触活性。虽然是神经精神疾病的遗传风险因素，CSMD1在神经发育障碍中的作用尚不清楚.通过国际变体共享，我们在六个不同血统的八个个体中鉴定了遗传的双等位基因CSMD1变异，这些个体具有全球发育迟缓，智力残疾,小头畸形,和Polymicrogyria。我们对从CSMD1敲除的人胚胎干细胞（hESC）分化的早期前脑器官中的CSMD1功能丧失（LOF）发病机理进行了建模。我们表明CSMD1对于神经上皮细胞结构和同步分化是必需的。总之,我们确定了CSMD1在脑发育和双等位基因CSMD1变异中的关键作用,作为先前未定义的神经发育障碍的分子基础.
