Publication Date
10-17-2023
Journal
Human Molecular Genetics
DOI
10.1093/hmg/ddad130
PMID
37552066
PMCID
PMC10586195
PubMedCentral® Posted Date
8-8-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Humans, Child, Zebrafish, Caenorhabditis elegans, Neurodevelopmental Disorders, Intellectual Disability, Phenotype, rab GTP-Binding Proteins, Megalencephaly, Developmental Disabilities, Mutation, Missense, rab5 GTP-Binding Proteins
Abstract
Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway.