By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model provides, we investigated RosaCre, NestinCre and NexCre driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.

中文翻译：

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KIF2A突变的条件转换为皮层畸形的致病性提供了新的见解。

通过使用Cre介导的基因开关技术，我们能够成功产生带有KIF2A p.His321Asp错义点变异体的条件性敲入小鼠，该变异体是在皮质发育异常的受试者中鉴定的。这些小鼠表现出神经解剖学异常和小头畸形，与行为缺陷和癫痫易感性有关，与所描述的人类表型有关。利用该模型提供的灵活性，我们研究了RosaCre，NestinCre和NexCre驱动的突变表达，以剖析神经发育皮质异常的病理生理机制。我们显示p.His321Asp致病变体的表达增加了凋亡，并在新生神经元中引起异常的多极至双极转变，因此，提供了见解，以更好地了解表征KIF2A相关人类疾病的皮质组织和脑部生长缺陷。我们进一步证明观察到的细胞表型可能与KIF2A的微管解聚功能不足有关。