RRC ID 51273
Author Marin-Valencia I, Gerondopoulos A, Zaki MS, Ben-Omran T, Almureikhi M, Demir E, Guemez-Gamboa A, Gregor A, Issa MY, Appelhof B, Roosing S, Musaev D, Rosti B, Wirth S, Stanley V, Baas F, Barr FA, Gleeson JG.
Title Homozygous Mutations in TBC1D23 Lead to a Non-degenerative Form of Pontocerebellar Hypoplasia.
Journal Am J Hum Genet
Abstract Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.
Volume 101(3)
Pages 441-450
Published 2017-9-7
DOI 10.1016/j.ajhg.2017.07.015
PII S0002-9297(17)30293-8
PMID 28823706
PMC PMC5590949
MeSH Adolescent Animals Cerebellar Diseases / genetics* Cerebellar Diseases / pathology Child Child, Preschool Female GTPase-Activating Proteins / genetics* HeLa Cells Homozygote* Humans Male Microcephaly / genetics* Microcephaly / pathology Mutation* Pedigree Phenotype Zebrafish / genetics Zebrafish / growth & development
IF 10.502
Times Cited 20
Zebrafish Tg(HuC:Kaede)