Recurrent KIF2A mutations are responsible for classic lissencephaly

• Published in: Neurogenetics Vol. 18; no. 2; pp. 73 - 79
• Main Authors: Cavallin, Mara, Bijlsma, Emilia K., El Morjani, Adrienne, Moutton, Sébastien, Peeters, Els A. J., Maillard, Camille, Pedespan, Jean Michel, Guerrot, Anne-Marie, Drouin-Garaud, Valérie, Coubes, Christine, Genevieve, David, Bole-Feysot, Christine, Fourrage, Cecile, Steffann, Julie, Bahi-Buisson, Nadia
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-04-2017; Springer Nature B.V; Springer Verlag
• Subjects: Adolescent; Biomedical and Life Sciences; Biomedicine; Classical Lissencephalies and Subcortical Band Heterotopias - genetics; DNA Mutational Analysis; Female; Gene Frequency; Genetics; Human Genetics; Human health and pathology; Humans; Infant; Kinesin - genetics; Life Sciences; Lissencephaly - genetics; Male; Molecular Medicine; Mutation, Missense; Neurons and Cognition; Neurosciences; Original Article; Polymorphism, Single Nucleotide; KIF2A; Lissencephaly; Kinesin
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-016-0499-8

Kinesins play a critical role in the organization and dynamics of the microtubule cytoskeleton, making them central players in neuronal proliferation, neuronal migration, and postmigrational development. Recently,
KIF2A
mutations were identified in cortical malformation syndromes associated with microcephaly. Here, we detected two de novo p.Ser317Asn and p.His321Pro mutations in
KIF2A
in two patients with lissencephaly and microcephaly. In parallel, we re-evaluated the two previously reported cases showing de novo mutations of the same residues. The identification of mutations only in the residues Ser317 and His321 suggests these are hotspots for de novo mutations. Both mutations lead to a classic form of lissencephaly, with a posterior to anterior gradient, almost indistinguishable from
LIS1-
related lissencephaly. However, three fourths of patients also showed variable congenital and postnatal microcephaly, up to −5 SD. Located in the motor domain of the KIF2A protein, the Ser317 and His321 alterations are expected to disrupt binding or hydrolysis of ATP and consequently the MT depolymerizing activity. This report also establishes that
KIF2A
mutations represent significant causes of classic lissencephaly with microcephaly.