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 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 Cowan; Nadia Bahi-Buisson; Jamel Chelly

doi:10.1038/ng.2613

Journal articles

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, *}

* Corresponding author

1 IC UM3 (UMR 8104 / U1016) - Institut Cochin

2 Department of Biochemistry and Molecular Pharmacology

3 INSERM U836, équipe 1, Physiopathologie du cytosquelette

GIN - Grenoble Institut des Neurosciences

4 Pediatric Neurology Unit and Laboratories

5 IRCCS - Istituto Di Ricovero e Cura a Carattere Scientifico

6 Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide

7 UOC - Unità Operativa Complessa di Neuropsichiatria Infantile

8 Département de Pédiatrie

9 Service de génétique

10 Mitochondrie : Régulations et Pathologie

11 Clinique Médicale Pédiatrique

12 Unité de Neurologie Pédiatrique

13 Service de Pédiatrie et de Génétique Médicale

14 L2C2 - Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition

15 Service de pédiatrie

16 Service Neuropédiatrie

17 BIP-D - Plate Forme Paris Descartes de Bioinformatique

18 CNG - Centre National de Génotypage

19 Institut du Fer à Moulin

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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Journal articles

Domain :

Life Sciences [q-bio] / Neurons and Cognition [q-bio.NC]

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https://www.hal.inserm.fr/inserm-00838073
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Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

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

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