Format

Send to

Choose Destination
Nat Commun. 2019 May 13;10(1):2129. doi: 10.1038/s41467-019-10081-8.

TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis.

Ivanova EL1,2,3,4, Gilet JG1,2,3,4, Sulimenko V5, Duchon A1,2,3,4, Rudolf G1,2,3,4, Runge K1,2,3,4, Collins SC1,2,3,4,6, Asselin L1,2,3,4, Broix L1,2,3,4, Drouot N1,2,3,4, Tilly P1,2,3,4, Nusbaum P7, Vincent A1,2,4, Magnant W1,2,4, Skory V1,2,3,4, Birling MC8, Pavlovic G8, Godin JD1,2,3,4, Yalcin B1,2,3,4, Hérault Y1,2,3,4, Dráber P5, Chelly J1,2,3,4,9,10, Hinckelmann MV11,12,13,14.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400, Illkirch, France.
2
Centre National de la Recherche Scientifique, UMR7104, 67400, Illkirch, France.
3
Institut National de la Santé et de la Recherche Médicale, U1258, 67400, Illkirch, France.
4
Université de Strasbourg, 67000, Strasbourg, France.
5
Institute of Molecular Genetics of the Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague, Czech Republic.
6
Université de Bourgogne, SVTE, Boulevard Gabriel, 21000, Dijon, France.
7
Service de Biochimie et de Génétique Moléculaire, Hôpital Cochin, AP-HP, Paris, 75014, France.
8
CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), 1 rue Laurent Fries, F-67404, Illkirch-Graffenstaden, France.
9
Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67000, Strasbourg, France.
10
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaire de Strasbourg, 67000, Strasbourg, France.
11
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400, Illkirch, France. hinckelm@igbmc.fr.
12
Centre National de la Recherche Scientifique, UMR7104, 67400, Illkirch, France. hinckelm@igbmc.fr.
13
Institut National de la Santé et de la Recherche Médicale, U1258, 67400, Illkirch, France. hinckelm@igbmc.fr.
14
Université de Strasbourg, 67000, Strasbourg, France. hinckelm@igbmc.fr.

Abstract

De novo heterozygous missense variants in the γ-tubulin gene TUBG1 have been linked to human malformations of cortical development associated with intellectual disability and epilepsy. Here, we investigated through in-utero electroporation and in-vivo studies, how four of these variants affect cortical development. We show that TUBG1 mutants affect neuronal positioning, disrupting the locomotion of new-born neurons but without affecting progenitors' proliferation. We further demonstrate that pathogenic TUBG1 variants are linked to reduced microtubule dynamics but without major structural nor functional centrosome defects in subject-derived fibroblasts. Additionally, we developed a knock-in Tubg1Y92C/+ mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1Y92C/+ animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1Y92C/+ mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center