Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

中文翻译：

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CEP85L 的致病变异导致散发性和家族性后显性无脑畸形。


无脑畸形（LIS），表示“光滑的大脑”，其特征是缺乏正常的大脑回旋以及皮质厚度异常。超过 20 个基因的致病变异与 LIS 相关。大多数后部为主的 LIS 是由 LIS1（也称为 PAFAH1B1）的致病性变异引起的，尽管很大一部分仍然没有已知的遗传病因。我们现在将 CEP85L 视为后部显性 LIS 的重要原因，并鉴定了 13 个具有罕见杂合 CEP85L 变异的个体，其中包括 2 个具有常染色体显性遗传的家族。我们发现 CEP85L 是一种定位于中心粒周围物质的中心体蛋白，Cep85L 的敲低会导致小鼠神经元迁移缺陷。 LIS1 也定位于中心体，表明该细胞器是后部优势 LIS 机制的关键。