Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A Cause Malformations of Cortical Development and Microcephaly

Overview

Journal Nat Genet

Specialty Genetics

Date 2013 Apr 23

PMID 23603762

Citations 223

Authors

Karine Poirier

Nicolas Lebrun

Loic Broix

Guoling Tian

Yoann Saillour

Cecile Boscheron

Elena Parrini

Stephanie Valence

Benjamin Saint Pierre

Madison Oger

Didier Lacombe

David Genevieve

Elena Fontana

Franscesca Darra

Claude Cances

Magalie Barth

Dominique Bonneau

Bernardo Dalla Bernadina

Sylvie Nguyen

Cyril Gitiaux

Philippe Parent

Vincent Des Portes

Jean Michel Pedespan

Victoire Legrez

Laetitia Castelnau-Ptakine

Patrick Nitschke

Thierry Hieu

Cecile Masson

Diana Zelenika

Annie Andrieux

Fiona Francis

Renzo Guerrini

Nicholas J Cowan

Nadia Bahi-Buisson

Jamel Chelly

Affiliations

Soon will be listed here.

Abstract

The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD.

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