RAB1A Haploinsufficiency Phenocopies the 2p14-p15 Microdeletion and Is Associated With Impaired Neuronal Differentiation

Authors

Jonathan J Rios
Yang Li
Nandina Paria
Ryan J Bohlender
Chad Huff
Jill A Rosenfeld
Pengfei Liu
Weimin Bi
Kentaro Haga
Mitsunori Fukuda
Shayal Vashisth
Kiran Kaur
Maria H Chahrour
Michael B Bober
Angela L Duker
Farah A Ladha
Neil A Hanchard
Kristhen Atala
Anas M Khanshour
Linsley Smith
Carol A Wise
Mauricio R Delgado

Publication Date

12-7-2023

Journal

American Journal of Human Genetics

Abstract

Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and a mosaic missense mutation (c.83T>C [p.Leu28Pro]), were identified in three individuals with similar neurodevelopmental presentations. In rescue experiments, production of the full-length, but not the truncated, RAB1a rescued Golgi structure and cell proliferation in Rab1-depleted cells. In contrast, the missense-variant RAB1a disrupted Golgi structure despite intact Rab1 expression, suggesting a dominant-negative function of the mosaic missense mutation. Knock-down of RAB1A in cultured human embryonic stem cell-derived neurons resulted in impaired neuronal arborization. Finally, RAB1A is located within the 2p14-p15 microdeletion syndrome locus. The similar clinical presentations of individuals with RAB1A loss-of-function mutations and the 2p14-p15 microdeletion syndrome implicate loss of RAB1A in the pathogenesis of neurodevelopmental manifestations of this microdeletion syndrome. Our study identifies a RAB1A-related neurocognitive disorder with speech and motor delay, demonstrates an essential role for RAB1a in neuronal differentiation, and implicates RAB1A in the etiology of the neurodevelopmental sequelae associated with the 2p14-p15 microdeletion syndrome.

Keywords

Child, Humans, Haploinsufficiency, Mutation, Mutation, Missense, rab GTP-Binding Proteins, Golgi Apparatus, Spastic Paraplegia, Hereditary, spastic paraplegia, microdeletion, neuronal differentiation

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Supplementary Materials

PMID: 37924809