Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

中文翻译：

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WDR81突变会导致人类成纤维细胞和果蝇神经干细胞中的极端小头畸形并损害有丝分裂进程

小脑小脑畸形是一种罕见的脑畸形，其特征是先天性小脑小畸形和小脑小脑畸形。怀疑小脑小脑症是由神经祖细胞的增殖或存活异常引起的。尽管最近鉴定出与小脑小脑症有关的六个基因，但对该病的病理生理基础仍知之甚少。我们对来自五个非小血缘家庭的七个受试者进行了基于三重的全外显子组测序，这些家族表现为小头畸形或小头畸形。这导致了WDR81中复合杂合突变的鉴定，先前与小脑性共济失调，智力障碍和四足运动有关的基因。患者的表型范围从严重的小头畸形，极小回转而伴小脑小脑发育不全到中度小头畸形伴小脑萎缩。在患者的成纤维细胞中，WDR81突变与有丝分裂指数增加和前中期/中期过渡延迟有关。同样，在体内，我们显示了果蝇WDR81直向同源基因的敲低导致神经干细胞的有丝分裂指数增加，而有丝分裂进程却延迟了。总而言之，我们重点介绍了WDR81-相关的脑畸形，包括小头畸形，中度到极度回旋以及小脑畸形。我们的结果表明，WDR81可能在果蝇和人类之间保守的有丝分裂中起作用。