دورية أكاديمية
أعرض في EDS

Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila.

التفاصيل البيبلوغرافية
العنوان: Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila.
المؤلفون: Straub J; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany., Konrad EDH; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany., Grüner J; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany., Toutain A; Service de Génétique, Centre Hospitalier Universitaire de Tours, 37044 Tours, France., Bok LA; Department of Pediatrics, Máxima Medical Center, 5504 DB Veldhoven, the Netherlands., Cho MT; GeneDx, Gaithersburg, MD 20877, USA., Crawford HP; Clinical and Metabolic Genetics, Cook Children's Medical Center, Fort Worth, TX 76102, USA., Dubbs H; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Douglas G; GeneDx, Gaithersburg, MD 20877, USA., Jobling R; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada., Johnson D; Sheffield Children's Hospital, Sheffield S10 2TH, UK., Krock B; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Mikati MA; Division of Pediatric Neurology, Duke University Medical Center, Durham, NC 27710, USA., Nesbitt A; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA., Nicolai J; Department of Neurology, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands., Phillips M; Clinical and Metabolic Genetics, Cook Children's Medical Center, Fort Worth, TX 76102, USA., Poduri A; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA., Ortiz-Gonzalez XR; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Pereleman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Powis Z; Ambry Genetics, Aliso Viejo, CA 92656, USA., Santani A; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA., Smith L; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA., Stegmann APA; Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands., Stumpel C; Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands., Vreeburg M; Department of Clinical Genetics and School for Oncology & Developmental Biology, Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands., Fliedner A; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany., Gregor A; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany., Sticht H; Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany., Zweier C; Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany. Electronic address: christiane.zweier@uk-erlangen.de.
مؤلفون مشاركون: Deciphering Developmental Disorders Study; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
المصدر: American journal of human genetics [Am J Hum Genet] 2018 Jan 04; Vol. 102 (1), pp. 44-57. Date of Electronic Publication: 2017 Dec 21.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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: Drosophila Proteins/*genetics , Drosophila melanogaster/*genetics , Epilepsy/*genetics , GTP-Binding Proteins/*genetics , Mutation, Missense/*genetics , Tumor Suppressor Proteins/*genetics, Adolescent ; Amino Acid Sequence ; Animals ; Behavior, Animal ; Child ; Child, Preschool ; Dendrites/metabolism ; Female ; GTP-Binding Proteins/chemistry ; Gene Dosage ; HEK293 Cells ; Humans ; Male ; Phenotype ; Synapses/pathology ; Tumor Suppressor Proteins/chemistry
مستخلص: Although the role of typical Rho GTPases and other Rho-linked proteins in synaptic plasticity and cognitive function and dysfunction is widely acknowledged, the role of atypical Rho GTPases (such as RHOBTB2) in neurodevelopment has barely been characterized. We have now identified de novo missense variants clustering in the BTB-domain-encoding region of RHOBTB2 in ten individuals with a similar phenotype, including early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorders. Three of the variants were recurrent. Upon transfection of HEK293 cells, we found that mutant RHOBTB2 was more abundant than the wild-type, most likely because of impaired degradation in the proteasome. Similarly, elevated amounts of the Drosophila ortholog RhoBTB in vivo were associated with seizure susceptibility and severe locomotor defects. Knockdown of RhoBTB in the Drosophila dendritic arborization neurons resulted in a decreased number of dendrites, thus suggesting a role of RhoBTB in dendritic development. We have established missense variants in the BTB-domain-encoding region of RHOBTB2 as causative for a developmental and epileptic encephalopathy and have elucidated the role of atypical Rho GTPase RhoBTB in Drosophila neurological function and possibly dendrite development.
(Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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معلومات مُعتمدة: United Kingdom WT_ Wellcome Trust; P40 OD018537 United States OD NIH HHS; R01 GM084947 United States GM NIGMS NIH HHS; T32 NS007413 United States NS NINDS NIH HHS
فهرسة مساهمة: Keywords: Drosophila melanogaster; RHOBTB2; epileptic Encephalopathy; intellectual disability; proteasom; ubiquitination
المشرفين على المادة: 0 (Drosophila Proteins)
0 (RHOBTB2 protein, human)
0 (RhoBTB protein, Drosophila)
0 (Tumor Suppressor Proteins)
EC 3.6.1.- (GTP-Binding Proteins)
تواريخ الأحداث: Date Created: 20171226 Date Completed: 20181211 Latest Revision: 20221006
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5777381
DOI: 10.1016/j.ajhg.2017.11.008
PMID: 29276004
قاعدة البيانات: MEDLINE
الوصف
تدمد:1537-6605
DOI:10.1016/j.ajhg.2017.11.008