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

Karine Poirier, Nicolas Lebrun, Loic Broix, Guoling Tian, Yoann Saillour, Cécile Boscheron, Elena Parrini, Stephanie Valence, Benjamin Saint Pierre, Madison Oger, Didier Lacombe, David Geneviève, Elena Fontana, Franscesca Darra, Claude Cances, Magalie Barth, Dominique Bonneau, Bernardo Dalla Bernadina, Sylvie N'Guyen, Cyril GitiauxPhilippe 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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)639-647
Number of pages9
JournalNature Genetics
Volume45
Issue number6
DOIs
Publication statusPublished - Jun 2013

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Malformations of Cortical Development
Microcephaly
Microtubules
Mutation
Microtubule Proteins
Saccharomyces cerevisiae Proteins
Germ-Line Mutation
Protein Folding
Missense Mutation
Tubulin
Hydrolysis
Adenosine Triphosphate
Recurrence
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., ... Chelly, J. (2013). Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nature Genetics, 45(6), 639-647. https://doi.org/10.1038/ng.2613

Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. / Poirier, Karine; Lebrun, Nicolas; Broix, Loic; Tian, Guoling; Saillour, Yoann; Boscheron, Cécile; Parrini, Elena; Valence, Stephanie; Pierre, Benjamin Saint; Oger, Madison; Lacombe, Didier; Geneviève, David; Fontana, Elena; Darra, Franscesca; Cances, Claude; Barth, Magalie; Bonneau, Dominique; Bernadina, Bernardo Dalla; N'Guyen, Sylvie; Gitiaux, Cyril; Parent, Philippe; Des Portes, Vincent; Pedespan, Jean Michel; Legrez, Victoire; Castelnau-Ptakine, Laetitia; Nitschke, Patrick; Hieu, Thierry; Masson, Cecile; Zelenika, Diana; Andrieux, Annie; Francis, Fiona; Guerrini, Renzo; Cowan, Nicholas J.; Bahi-Buisson, Nadia; Chelly, Jamel.

In: Nature Genetics, Vol. 45, No. 6, 06.2013, p. 639-647.

Research output: Contribution to journalArticle

Poirier, K, Lebrun, N, Broix, L, Tian, G, Saillour, Y, Boscheron, C, Parrini, E, Valence, S, Pierre, BS, Oger, M, Lacombe, D, Geneviève, D, Fontana, E, Darra, F, Cances, C, Barth, M, Bonneau, D, Bernadina, BD, N'Guyen, S, Gitiaux, C, Parent, P, Des Portes, V, Pedespan, JM, Legrez, V, Castelnau-Ptakine, L, Nitschke, P, Hieu, T, Masson, C, Zelenika, D, Andrieux, A, Francis, F, Guerrini, R, Cowan, NJ, Bahi-Buisson, N & Chelly, J 2013, 'Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly', Nature Genetics, vol. 45, no. 6, pp. 639-647. https://doi.org/10.1038/ng.2613
Poirier, Karine ; Lebrun, Nicolas ; Broix, Loic ; Tian, Guoling ; Saillour, Yoann ; Boscheron, Cécile ; Parrini, Elena ; Valence, Stephanie ; Pierre, Benjamin Saint ; Oger, Madison ; Lacombe, Didier ; Geneviève, David ; Fontana, Elena ; Darra, Franscesca ; Cances, Claude ; Barth, Magalie ; Bonneau, Dominique ; Bernadina, Bernardo Dalla ; N'Guyen, Sylvie ; Gitiaux, Cyril ; Parent, Philippe ; Des Portes, Vincent ; Pedespan, Jean Michel ; Legrez, Victoire ; Castelnau-Ptakine, Laetitia ; Nitschke, Patrick ; Hieu, Thierry ; Masson, Cecile ; Zelenika, Diana ; Andrieux, Annie ; Francis, Fiona ; Guerrini, Renzo ; Cowan, Nicholas J. ; Bahi-Buisson, Nadia ; Chelly, Jamel. / Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. In: Nature Genetics. 2013 ; Vol. 45, No. 6. pp. 639-647.
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AU - Tian, Guoling

AU - Saillour, Yoann

AU - Boscheron, Cécile

AU - Parrini, Elena

AU - Valence, Stephanie

AU - Pierre, Benjamin Saint

AU - Oger, Madison

AU - Lacombe, Didier

AU - Geneviève, David

AU - Fontana, Elena

AU - Darra, Franscesca

AU - Cances, Claude

AU - Barth, Magalie

AU - Bonneau, Dominique

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AU - N'Guyen, Sylvie

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AU - Pedespan, Jean Michel

AU - Legrez, Victoire

AU - Castelnau-Ptakine, Laetitia

AU - Nitschke, Patrick

AU - Hieu, Thierry

AU - Masson, Cecile

AU - Zelenika, Diana

AU - Andrieux, Annie

AU - Francis, Fiona

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