title: Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.
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.
authors.affiliation: Institut Cochin, Université Paris-Descartes, Centre National de la Recherche Scientifique CNRS, UMR 8104, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Poirier
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lebrun
authors.forename: Loic
authors.initials: L
authors.lastname: Broix
authors.forename: Guoling
authors.initials: G
authors.lastname: Tian
authors.forename: Yoann
authors.initials: Y
authors.lastname: Saillour
authors.forename: Cécile
authors.initials: C
authors.lastname: Boscheron
authors.forename: Elena
authors.initials: E
authors.lastname: Parrini
authors.forename: Stephanie
authors.initials: S
authors.lastname: Valence
authors.forename: Benjamin Saint
authors.initials: BS
authors.lastname: Pierre
authors.forename: Madison
authors.initials: M
authors.lastname: Oger
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: David
authors.initials: D
authors.lastname: Geneviève
authors.forename: Elena
authors.initials: E
authors.lastname: Fontana
authors.forename: Franscesca
authors.initials: F
authors.lastname: Darra
authors.forename: Claude
authors.initials: C
authors.lastname: Cances
authors.forename: Magalie
authors.initials: M
authors.lastname: Barth
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Bernardo Dalla
authors.initials: BD
authors.lastname: Bernadina
authors.forename: Sylvie
authors.initials: S
authors.lastname: N'guyen
authors.forename: Cyril
authors.initials: C
authors.lastname: Gitiaux
authors.forename: Philippe
authors.initials: P
authors.lastname: Parent
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Pedespan
authors.forename: Victoire
authors.initials: V
authors.lastname: Legrez
authors.forename: Laetitia
authors.initials: L
authors.lastname: Castelnau-Ptakine
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.forename: Thierry
authors.initials: T
authors.lastname: Hieu
authors.forename: Cecile
authors.initials: C
authors.lastname: Masson
authors.forename: Diana
authors.initials: D
authors.lastname: Zelenika
authors.forename: Annie
authors.initials: A
authors.lastname: Andrieux
authors.forename: Fiona
authors.initials: F
authors.lastname: Francis
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Cowan
authors.forename: Nadia
authors.initials: N
authors.lastname: Bahi-Buisson
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
mesh_terms: D000818:Animals; D019556:COS Cells; D002465:Cell Movement; D002522:Chlorocebus aethiops; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D059472:Exome; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D054082:Lissencephaly / Q000235:genetics / Q000473:pathology; D008279:Magnetic Resonance Imaging; D054220:Malformations of Cortical Development / Q000235:genetics / Q000473:pathology; D051379:Mice; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D020125:Mutation, Missense; D059906:Neuroimaging; D010375:Pedigree; D017422:Sequence Analysis, DNA; D014404:Tubulin / Q000235:genetics*
chemical_list: C511240:DYNC1H1 protein, human; C509805:KIF2A protein, human; C582625:TUBG1 protein, human; D014404:Tubulin; C514435:KIF5C protein, human; D056445:Cytoplasmic Dyneins; D016547:Kinesins