دورية أكاديمية
RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation.
| العنوان: | RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation. |
|---|---|
| المؤلفون: | 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. |
| المصدر: | 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. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2008- : [Cambridge, MA] : Cell Press Original Publication: Baltimore, American Society of Human Genetics. |
| مواضيع طبية MeSH: | Haploinsufficiency*/genetics , Spastic Paraplegia, Hereditary*/genetics, Child ; Humans ; Mutation ; Mutation, Missense/genetics ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism ; Golgi Apparatus/metabolism |
| مستخلص: | 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.) |
| References: | Nat Biotechnol. 2014 Jul;32(7):663-9. (PMID: 24837662) Neurology. 2001 Feb 27;56(4):467-71. (PMID: 11222789) Neurogenetics. 2004 Sep;5(3):157-64. (PMID: 15248095) JAMA. 2014 Nov 12;312(18):1870-9. (PMID: 25326635) Curr Opin Neurol. 2007 Dec;20(6):674-80. (PMID: 17992088) Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9800-5. (PMID: 23716696) Am J Hum Genet. 2014 Feb 6;94(2):268-77. (PMID: 24388663) Clin Genet. 2013 Mar;83(3):257-62. (PMID: 22571692) Nat Rev Mol Cell Biol. 2009 Aug;10(8):513-25. (PMID: 19603039) Eur J Hum Genet. 2014 Oct;22(10):1180-4. (PMID: 24473461) G3 (Bethesda). 2012 Nov;2(11):1415-25. (PMID: 23173093) Hum Mutat. 2020 Feb;41(2):487-501. (PMID: 31692161) Nat Rev Neurosci. 2011 Jan;12(1):31-42. (PMID: 21139634) J Clin Invest. 2010 Apr;120(4):1097-110. (PMID: 20200447) J Cell Sci. 2021 Dec 15;134(24):. (PMID: 34817057) Gene. 2013 Mar 1;516(1):158-61. (PMID: 23266801) Neurology. 2004 Jun 8;62(11):2138-9. (PMID: 15184642) Nature. 2016 Aug 17;536(7616):285-91. (PMID: 27535533) J Cell Biol. 2019 Jun 3;218(6):2035-2050. (PMID: 31072826) Science. 2006 Jul 21;313(5785):324-8. (PMID: 16794039) Semin Neurol. 2014 Jul;34(3):293-305. (PMID: 25192507) Curr Biol. 2011 Oct 25;21(20):1704-15. (PMID: 22000105) Eur J Med Genet. 2011 Jan-Feb;54(1):67-72. (PMID: 20950717) Hum Mol Genet. 2006 Apr 15;15(8):1343-53. (PMID: 16537571) Eur J Hum Genet. 2017 Feb;25(3):393. (PMID: 28179632) Mol Cell Biol. 1987 Jul;7(7):2367-77. (PMID: 3302675) J Med Genet. 2000 Oct;37(10):759-65. (PMID: 11015453) Mol Biol Cell. 2006 Apr;17(4):1514-26. (PMID: 16421253) Mol Biol Cell. 2003 May;14(5):1882-99. (PMID: 12802062) Nat Commun. 2017 Jan 16;8:14049. (PMID: 28091601) Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7811-6. (PMID: 20375281) Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11963-7. (PMID: 7991565) PLoS One. 2014 Sep 09;9(9):e107028. (PMID: 25203062) Annu Rev Neurosci. 2012;35:25-47. (PMID: 22540978) |
| معلومات مُعتمدة: | F31 HD110206 United States HD NICHD NIH HHS; R01 HD099162 United States HD NICHD NIH HHS |
| فهرسة مساهمة: | Keywords: microdeletion; neuronal differentiation; spastic paraplegia |
| المشرفين على المادة: | EC 3.6.5.2 (rab GTP-Binding Proteins) |
| تواريخ الأحداث: | Date Created: 20231104 Date Completed: 20231216 Latest Revision: 20240725 |
| رمز التحديث: | 20240726 |
| مُعرف محوري في PubMed: | PMC10722380 |
| DOI: | 10.1016/j.ajhg.2023.10.009 |
| PMID: | 37924809 |
| قاعدة البيانات: | MEDLINE |
كن أول من يترك تعليقا!