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

Ekaterina L. Ivanova, Johan G. Gilet, Vadym Sulimenko, Arnaud Duchon, Gabrielle Rudolf, Karen Runge, Stephan C. Collins, Laure Asselin, Loic Broix, Nathalie Drouot, Peggy Tilly, Patrick Nusbaum, Alexandre Vincent, William Magnant, Valerie Skory, Marie-Christine Birling, Guillaume Pavlovic, Juliette D. Godin, Binnaz Yalcin, Yann Hérault, Pavel Dráber, Jamel Chelly and Maria-Victoria Hinckelmann ()
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Ekaterina L. Ivanova: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Johan G. Gilet: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Vadym Sulimenko: Institute of Molecular Genetics of the Czech Academy of Sciences
Arnaud Duchon: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Gabrielle Rudolf: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Karen Runge: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Stephan C. Collins: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Laure Asselin: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Loic Broix: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Nathalie Drouot: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Peggy Tilly: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Patrick Nusbaum: Hôpital Cochin, AP-HP
Alexandre Vincent: Institut de Génétique et de Biologie Moléculaire et Cellulaire
William Magnant: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Valerie Skory: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Marie-Christine Birling: CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS)
Guillaume Pavlovic: CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS)
Juliette D. Godin: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Binnaz Yalcin: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Yann Hérault: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Pavel Dráber: Institute of Molecular Genetics of the Czech Academy of Sciences
Jamel Chelly: Institut de Génétique et de Biologie Moléculaire et Cellulaire
Maria-Victoria Hinckelmann: Institut de Génétique et de Biologie Moléculaire et Cellulaire

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10081-8

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