TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis
Jazyk angličtina Země Velká Británie, Anglie Médium electronic
Typ dokumentu časopisecké články, práce podpořená grantem, audiovizuální média
PubMed
31086189
PubMed Central
PMC6513894
DOI
10.1038/s41467-019-10081-8
PII: 10.1038/s41467-019-10081-8
Knihovny.cz E-zdroje
- MeSH
- centrozom metabolismus MeSH
- chování zvířat MeSH
- elektronová mikroskopie MeSH
- embryo savčí MeSH
- epilepsie genetika MeSH
- fibroblasty cytologie metabolismus ultrastruktura MeSH
- genetická predispozice k nemoci MeSH
- genový knockin MeSH
- HeLa buňky MeSH
- intravitální mikroskopie MeSH
- konfokální mikroskopie MeSH
- lidé MeSH
- malformace mozkové kůry genetika MeSH
- mikrotubuly genetika metabolismus MeSH
- missense mutace MeSH
- modely nemocí na zvířatech MeSH
- mozková kůra abnormality cytologie diagnostické zobrazování MeSH
- myši transgenní MeSH
- myši MeSH
- neurogeneze genetika MeSH
- neurony fyziologie MeSH
- pohyb buněk genetika MeSH
- tubulin genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- TUBG1 protein, human MeSH Prohlížeč
- TUBG1 protein, mouse MeSH Prohlížeč
- tubulin MeSH
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.
Centre National de la Recherche Scientifique UMR7104 67400 Illkirch France
Institut de Génétique et de Biologie Moléculaire et Cellulaire 67400 Illkirch France
Institut National de la Santé et de la Recherche Médicale U1258 67400 Illkirch France
Laboratoire de Diagnostic Génétique Hôpitaux Universitaire de Strasbourg 67000 Strasbourg France
Service de Biochimie et de Génétique Moléculaire Hôpital Cochin AP HP Paris 75014 France
Université de Bourgogne SVTE Boulevard Gabriel 21000 Dijon France
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