Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

Karine Poirier 1 Nicolas Lebrun 1 Loic Broix 1 Guoling Tian 2 Yoann Saillour 1 Cécile Boscheron 3 Elena Parrini 4, 5 Stephanie Valence 1 Benjamin Saint Pierre 1 Madison Oger 1 Didier Lacombe 6 David Geneviève 6 Elena Fontana 7 Franscesca Darra 7 Claude Cances 8 Magalie Barth 9, 10 Dominique Bonneau 9, 10 Bernardo Dalla Bernadina 7 Sylvie N'Guyen 11 Cyril Gitiaux 1, 12 Philippe Parent 13 Vincent Des Portes 14 Jean Michel Pedespan 15 Victoire Legrez 16 Laetitia Castelnau-Ptakine 1 Patrick Nitschke 17 Thierry Hieu 17 Cecile Masson 17 Diana Zelenika 18 Annie Andrieux 3 Fiona Francis 19 Renzo Guerrini 5 Nicholas Cowan 2, * Nadia Bahi-Buisson 1, 12 Jamel Chelly 1, *
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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Nature Genetics, Nature Publishing Group, 2013, 45 (6), pp.639-47. 〈10.1038/ng.2613〉
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Karine Poirier, Nicolas Lebrun, Loic Broix, Guoling Tian, Yoann Saillour, et al.. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.. Nature Genetics, Nature Publishing Group, 2013, 45 (6), pp.639-47. 〈10.1038/ng.2613〉. 〈inserm-00838073〉

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