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Free keywords:
Adolescent
Animals
Cells, Cultured
Cerebellar Diseases/*genetics/pathology
Cerebellum/*abnormalities/pathology
Child
Child, Preschool
Developmental Disabilities/genetics/pathology
Embryo, Mammalian/metabolism/pathology
Female
GTPase-Activating Proteins/*genetics
*Homozygote
Humans
Intellectual Disability/genetics/pathology
Male
Mice
Microcephaly/*genetics/pathology
*Mutation
Nervous System Malformations/*genetics/pathology
Neuroblastoma/genetics/pathology
Neuronal Outgrowth
Neurons/metabolism/*pathology
Pedigree
Tbc1d23
microcephaly
pontocerebellar hypoplasia
small normally proportioned cerebellum
Abstract:
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.
