RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation

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

doi:10.1016/j.ajhg.2023.10.009

RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation

Am J Hum Genet. 2023 Dec 7;110(12):2103-2111. doi: 10.1016/j.ajhg.2023.10.009. Epub 2023 Nov 3.

Authors

Jonathan J Rios¹, Yang Li², Nandina Paria², Ryan J Bohlender³, Chad Huff³, Jill A Rosenfeld⁴, Pengfei Liu⁴, Weimin Bi⁴, Kentaro Haga⁵, Mitsunori Fukuda⁵, Shayal Vashisth⁶, Kiran Kaur⁷, Maria H Chahrour⁸, Michael B Bober⁹, Angela L Duker¹⁰, Farah A Ladha¹¹, Neil A Hanchard¹¹, Kristhen Atala², Anas M Khanshour², Linsley Smith¹², Carol A Wise¹³, Mauricio R Delgado¹⁴

Affiliations

¹ Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Departments of Pediatrics University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: jonathan.rios@tsrh.org.
² Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA.
³ Department of Epidemiology, MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
⁵ Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.
⁶ Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁸ Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Peter O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁹ Nemours Children's Hospital, Wilmington, DE 19803, USA; Thomas Jefferson University, Philadelphia, PA 19144, USA.
¹⁰ Nemours Children's Hospital, Wilmington, DE 19803, USA.
¹¹ Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
¹² Department of Neurology, Scottish Rite for Children, Dallas, TX 75219, USA.
¹³ Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Departments of Pediatrics University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁴ Department of Neurology, Scottish Rite for Children, Dallas, TX 75219, USA; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

PMID: 37924809
PMCID: PMC10722380 (available on 2024-06-07)
DOI: 10.1016/j.ajhg.2023.10.009

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: microdeletion; neuronal differentiation; spastic paraplegia.

MeSH terms

Child
Golgi Apparatus / metabolism
Haploinsufficiency* / genetics
Humans
Mutation
Mutation, Missense / genetics
Spastic Paraplegia, Hereditary* / genetics
rab GTP-Binding Proteins / genetics
rab GTP-Binding Proteins / metabolism

Substances

rab GTP-Binding Proteins

Abstract

MeSH terms

Substances

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