Tian Guoling, Cristancho Ana G, Dubbs Holly A, Liu Grant T, Cowan Nicholas J, Goldberg Ethan M
Department of Molecular Pharmacology and Biochemistry New York University Langone Medical center New York New York 10016.
Department of Pediatrics Division of Neurology The Children's Hospital of Philadelphia Philadelphia Pennsylvania 19104.
Mol Genet Genomic Med. 2016 Sep 28;4(6):599-603. doi: 10.1002/mgg3.236. eCollection 2016 Nov.
Microtubules are dynamic polymers of / tubulin heterodimers that play a critical role in cerebral cortical development, by regulating neuronal migration, differentiation, and morphogenesis. Mutations in genes that encode either - or -tubulin or a spectrum of proteins involved in the regulation of microtubule dynamics lead to clinically devastating malformations of cortical development, including lissencephaly.
This is a single case report or a patient with lissencephaly, developmental delay, nystagmus, persistent hyperplastic primary vitreous, and infantile spasms, and undertook a neurogenetic workup. We include studies of mutant function in and HeLa cells.
The patient was found to have a novel de novo mutation in kinesin family member 2A (). This mutation results in a substitution of isoleucine at a highly conserved threonine residue within the ATP-binding domain. The KIF2A p.Thr320Ile mutant protein exhibited abnormal solubility, and KIF2A p.Thr320Ile overexpression in cultured cells led to the formation of aberrant microtubule networks.
Findings support the pathogenic link between mutation and lissencephaly, and expand the range of presentation to include infantile spasms and congenital anomalies.
微管是α/β微管蛋白异二聚体的动态聚合物，通过调节神经元迁移、分化和形态发生，在大脑皮质发育中起关键作用。编码α-或β-微管蛋白的基因或一系列参与微管动力学调节的蛋白质发生突变，会导致临床上具有毁灭性的皮质发育畸形，包括无脑回畸形。
这是一份关于一名患有无脑回畸形、发育迟缓、眼球震颤、永存原始玻璃体增生症和婴儿痉挛症患者的单病例报告，并进行了神经遗传学检查。我们纳入了对α和HeLa细胞中突变功能的研究。
发现该患者在驱动蛋白家族成员2A（KIF2A）中存在一种新的从头突变。此突变导致在ATP结合域内一个高度保守的苏氨酸残基处异亮氨酸替代。KIF2A p.Thr320Ile突变蛋白表现出异常的溶解性，并且在培养细胞中过表达KIF2A p.Thr320Ile会导致异常微管网络的形成。
研究结果支持KIF2A突变与无脑回畸形之间的致病联系，并扩大了临床表现范围，包括婴儿痉挛症和先天性异常。
