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TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis
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SYSNO ASEP 0505195 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis Author(s) Ivanova, E.L. (FR)
Gilet, J.G. (FR)
Sulimenko, Vadym (UMG-J) RID, ORCID
Duchon, A. (FR)
Rudolf, G. (FR)
Runge, K. (FR)
Collins s, S.C. (FR)
Asselin, L. (FR)
Broix, L. (FR)
Drouot, N. (FR)
Tiiiy, P. (FR)
Nusbaum, P. (FR)
Vincent, A. (FR)
Magnant, W. (FR)
Skory, V. (FR)
Birling, M.C. (FR)
Pavlovic, G. (FR)
Godin, J.D. (FR)
Yalcin, B. (FR)
Herault, Y. (FR)
Dráber, Pavel (UMG-J) RID, ORCID
Chelly, J. (FR)
Hinckelmann, M.V. (FR)Number of authors 23 Article number 2129 Source Title Nature Communications. - : Nature Publishing Group
Roč. 10, č. 1 (2019)Number of pages 18 s. Publication form Online - E Language eng - English Country GB - United Kingdom Keywords developing mouse-brain ; tubulin small complex ; spindle pole body ; gamma-tubulin ; centrosomal protein ; animal-models ; mutations ; mice ; migration ; gene Subject RIV EB - Genetics ; Molecular Biology OECD category Cell biology R&D Projects GA16-23702S GA ČR - Czech Science Foundation (CSF) GA18-27197S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000467702800002 DOI 10.1038/s41467-019-10081-8 Annotation De novo heterozygous missense variants in the gamma-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 Tubg1(Y)(92)(C/+) mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1(Y)(92)(C/+) animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1(Y)(92)(C/+) mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2020 Electronic address https://www.nature.com/articles/s41467-019-10081-8
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