Contributors: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC); Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS); Czech Academy of Sciences Prague (CAS); UFR Sciences de la Vie, de la Terre et de l'Environnement (Université de Bourgogne) (UFR SVTE); Université de Bourgogne (UB); Hôpital Cochin AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Institut Clinique de la Souris (ICS); French National Infrastructure for Mouse Phenogenomics (PHENOMIN); Fédération de Médecine Translationnelle de Strasbourg (FMTS); Université de Strasbourg (UNISTRA); Les Hôpitaux Universitaires de Strasbourg (HUS); ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010); ANR-10-INBS-0007,PHENOMIN,INFRASTRUCTURE NATIONALE EN PHENOGENOMIQUE SOURIS(2010); ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010)
نبذة مختصرة : International audience ; 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.
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