Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development.
Fiche publication
Date publication
septembre 2017
Journal
American journal of human genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHELLY Jamel
Tous les auteurs :
Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, Schaefer E, de Saint Martin A, Runge K, Iqbal Z, Spitz MA, Laura M, Drouot N, Gérard B, Deleuze JF, de Brouwer APM, Razzaq A, Dollfus H, Assir MZ, Nitchké P, Hinckelmann MV, Ropers H, Riazuddin S, Najmabadi H, van Bokhoven H, Chelly J
Lien Pubmed
Résumé
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.
Mots clés
Adolescent, Animals, Cells, Cultured, Cerebellar Diseases, genetics, Cerebellum, abnormalities, Child, Child, Preschool, Developmental Disabilities, genetics, Embryo, Mammalian, metabolism, Female, GTPase-Activating Proteins, genetics, Homozygote, Humans, Intellectual Disability, genetics, Male, Mice, Microcephaly, genetics, Mutation, Nervous System Malformations, genetics, Neuroblastoma, genetics, Neuronal Outgrowth, Neurons, metabolism, Pedigree
Référence
Am. J. Hum. Genet.. 2017 Sep 7;101(3):428-440