| First Author | Ivanova EL | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 2129 |
| PubMed ID | 31086189 | Mgi Jnum | J:275532 |
| Mgi Id | MGI:6305559 | Doi | 10.1038/s41467-019-10081-8 |
| Citation | Ivanova EL, et al. (2019) TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis. Nat Commun 10(1):2129 |
| abstractText | 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(Y92C/+) mouse model and assessed consequences of the mutation. Although centrosomal positioning in bipolar neurons is correct, they fail to initiate locomotion. Furthermore, Tubg1(Y92C/+) animals show neuroanatomical and behavioral defects and increased epileptic cortical activity. We show that Tubg1(Y92C/+) mice partially mimic the human phenotype and therefore represent a relevant model for further investigations of the physiopathology of cortical malformations. |
