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

Autor:	Rios JJ; 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., Li Y; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA., Paria N; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA., Bohlender RJ; Department of Epidemiology, MD Anderson Cancer Center, Houston, TX 77030, USA., Huff C; Department of Epidemiology, MD Anderson Cancer Center, Houston, TX 77030, USA., Rosenfeld JA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA., Liu P; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA., Bi W; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA., Haga K; Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan., Fukuda M; Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan., Vashisth S; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Kaur K; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA., Chahrour MH; 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., Bober MB; Nemours Children's Hospital, Wilmington, DE 19803, USA; Thomas Jefferson University, Philadelphia, PA 19144, USA., Duker AL; Nemours Children's Hospital, Wilmington, DE 19803, USA., Ladha FA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Hanchard NA; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Atala K; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA., Khanshour AM; Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, TX 75219, USA., Smith L; Department of Neurology, Scottish Rite for Children, Dallas, TX 75219, USA., Wise CA; 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., Delgado MR; 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.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2023 Dec 07; Vol. 110 (12), pp. 2103-2111. Date of Electronic Publication: 2023 Nov 03.
DOI:	10.1016/j.ajhg.2023.10.009
Abstrakt:	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. Competing Interests: Declaration of interests J.A.R., P.L., and W.B.: The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing completed at Baylor Genetics Laboratory. P.L. and W.B.: Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs genetic testing and derives revenue. P.L. and W.B. are employees of BCM and derive support through a professional services agreement with Baylor Genetics. (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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