Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants.
| Autor: | Mohammadi NA; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark., Ahring PK; School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia., Yu Liao VW; School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia., Chua HC; Sydney Pharmacy School, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia., Ortiz de la Rosa S; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark., Johannesen KM; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark., Michaeli-Yossef Y; Pediatric Neurology Unit and Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel., Vincent-Devulder A; Genetic Department, CHU Côte de Nacre, Caen, France., Meridda C; Genetic Department, CHU Côte de Nacre, Caen, France., Bruel AL; Genetic Department, CHU Côte de Nacre, Caen, France., Rossi A; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Pediatric Clinic, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy., Patel C; Genetic Health Queensland, Royal Brisbane & Women's Hospital, Brisbane, QLD 4029, Australia., Klepper J; Children's Hospital Aschaffenburg-Alzenau, Aschaffenburg, Germany., Bonanni P; IRCCS E. Medea Scientific Institute, Epilepsy Unit, Conegliano, Treviso, Italy., Minghetti S; IRCCS E. Medea Scientific Institute, Clinical Neurophysiology Unit, Bosisio Parini, LC, Italy., Trivisano M; Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy., Specchio N; Neurology, Epilepsy and Movement Disorders, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy., Amor D; Murdoch Children's Research Institute, Melbourne, Australia., Auvin S; Université de Paris, Child Neurology & Epilepsy, Paris, France; Robert-Debré Hospital, Center for Rare Epilepsies - Pediatric Neurology, Paris, France., Baer S; Department of Paediatric Neurology, French Reference Center of Rare Epilepsies CREER, Hôpitaux Universitaires de Strasbourg, Strasbourg, France., Meyer P; Paediatric Neurology Department, Phymedexp, Montpellier University, Inserm, CNRS, University Hospital Montpellier, Montpellier, France., Milh M; Department of Pediatric Neurology, AP-HM, La Timone Children's Hospital, Marseille, France; Faculté de Médecine Timone, Aix Marseille Univ, INSERM, MMG, U1251, ERN EpiCARE, Marseille, France., Salpietro V; Department of Neurosciences Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy; Pediatric Neurology and Muscular Diseases Unit, IRCCS Giannina Gaslini Institute, Genoa, Italy., Maroofian R; Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK., Lemke JR; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany., Weckhuysen S; Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital, Antwerp, Belgium; Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium., Christophersen P; Saniona A/S, Ballerup, Denmark., Rubboli G; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Chebib M; School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia., Jensen AA; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Absalom NL; School of Medical Sciences, Faculty of Medicine and Health, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales 2006, Australia; School of Science, Western Sydney University, Sydney, Australia. Electronic address: N.Absalom@westernsydney.edu.au., Møller RS; Department of Epilepsy Genetics and Personalized Treatment, Danish Epilepsy Centre, Filadelfia (Member of the ERN EpiCARE), Dianalund, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark. Electronic address: rimo@filadelfia.dk. |
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| Jazyk: | angličtina |
| Zdroj: | EBioMedicine [EBioMedicine] 2024 Aug; Vol. 106, pp. 105236. Date of Electronic Publication: 2024 Jul 11. |
| DOI: | 10.1016/j.ebiom.2024.105236 |
| Abstrakt: | Background: Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABA Methods: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Findings: Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. Interpretation: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. Funding: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation. Competing Interests: Declaration of interests SOR is the chair of the Young Epilepsy Section, ILAE, and has received consulting fees from Biopas-UCB, support for attending meetings and/or travel from Mythotherapies, and speaker fees from Abbott, LivaNova, Sanofi, Biopas-UCB and Nutricia. MT has received consulting fees from Biomarin, support for attending meetings and/or travel from Biomarin and Jazz Pharmaceuticals, and participated in Data Safety Monitoring Boards or Advisory Boards for Biocodex. SA is the deputy editor of Epilepsia, and has received consulting fees from UCB, Xenon, Encoded Therapeutics, EISAI, Stoke, Proveca, speaker fees from Biocodex, EISAI, Jazz Pharmaceuticals, Neuraxpharm, Nutricia and UCB and participated in Data Safety Monitoring Boards or Advisory Boards for GRIN Therapeutics. JK has received consulting fees from Biomarin, support for attending meetings and/or travel from Biomarin and Jazz Pharmaceuticals, and participated in Data Safety Monitoring Boards or Advisory Boards for Biocodex. SW has received consulting fees from UCB, Knopp Biosciences, Encoded Therapeutics, Roche, support for attending meetings and/or travel from Angelini Pharma, and participated in Data Safety Monitoring Boards or Advisory Boards for Angelini Pharma and Xenon Pharmaceuticals. NS has received consulting fees from Biomarin, support for attending meetings and/or travel from Biomarin and Jazz Pharmaceuticals, and participated in Data Safety Monitoring Boards or Advisory Boards for Biocodex. PB has received consulting fees from LivaNova, EISAI, Jazz Pharmaceuticals, Angelini Pharma and support for attending meetings and/or travel from Angelini Pharma and EISAI. RSM has received consulting fees from UCB, Orion, Saniona, Immedica and Atalanta, and speaker fees from EISAI, Angelini Pharma, Jazz Pharmaceuticals, Orion and UCB. PC is Executive Vice President, Research at the company Saniona in Denmark. The remaining authors declare no competing interests. (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Databáze: | MEDLINE |
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