WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells. - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Brain - A Journal of Neurology Année : 2017

WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells.

Thomas Besnard
Alice Kuster
  • Fonction : Auteur
  • PersonId : 1202952

Résumé

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

Dates et versions

hal-02620552 , version 1 (25-05-2020)

Identifiants

Citer

Mara Cavallin, Maria A Rujano, Nathalie Bednarek, Daniel Medina-Cano, Antoinette Bernabe Gelot, et al.. WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells.. Brain - A Journal of Neurology , 2017, 140 (10), pp.2597-2609. ⟨10.1093/brain/awx218⟩. ⟨hal-02620552⟩
82 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More