A patient with lissencephaly, developmental delay, and infantile spasms, due to de novo heterozygous mutation of KIF2A

Mol Genet Genomic Med. 2016 Sep 28;4(6):599-603. doi: 10.1002/mgg3.236. eCollection 2016 Nov.


Background: Microtubules are dynamic polymers of α/β tubulin heterodimers that play a critical role in cerebral cortical development, by regulating neuronal migration, differentiation, and morphogenesis. Mutations in genes that encode either α- or β-tubulin or a spectrum of proteins involved in the regulation of microtubule dynamics lead to clinically devastating malformations of cortical development, including lissencephaly.

Methods: 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 Escherichia coli and HeLa cells.

Results: The patient was found to have a novel de novo mutation in kinesin family member 2A (KIF2A). 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.

Conclusion: Findings support the pathogenic link between KIF2A mutation and lissencephaly, and expand the range of presentation to include infantile spasms and congenital anomalies.

Keywords: Brain development; KIF2A; lissencephaly; microtubules.