From the Departments of Neurology and Epileptology (N.S., S.S., U.B.S.H., H.L., Y.W.) and Neurodegenerative Diseases (E.L.), Hertie-Institute for Clinical Brain Research, University of Tübingen; Institute of Clinical Molecular Biology (M.P., I.H.), Christian-Albrechts-University of Kiel; Departments of Neuropediatrics (M.P., A.V.R., H.M., I.H.) and Pediatrics I (A.V.R.), University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel; Cologne Center for Genomics (T.B., D.L.), University of Cologne, Germany; Epilepsy Center SEIN (P.B.A.), Heemstede, the Netherlands; Epilepsiezentrum Bodensee (H.B.), Weissenau, Germany; Department of Genetics and Precision Medicine (A.B.), Danish Epilepsy Centre, Dianalund, Denmark; IRCCS Istituti delle Scienze Neurologiche di Bologna (F.B., L.L., R.M., P.T.); Department of Biomedical and Neuromotor Sciences (F.B., L.L., P.T.), University of Bologna, Italy; Department of Biomedical Sciences (R.J.B.), Cooper Medical School of Rowan University, Camden, NJ; Pediatric Neurology Unit (B.Z.B., G.H.), Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat Gan; Sackler School of Medicine (B.Z.B., G.H.), Tel Aviv University, Israel; FutureNeuro SFI Research Centre (M.G.D., H.K.) and Department of Neurology, Beaumont Hospital (M.G.D., H.K.), Royal College of Surgeons in Ireland; StAR MD Programme (M.G.D.), Royal College of Surgeons in Ireland in collaboration with Blackrock Clinic, Dublin, Ireland; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, and Department of Neuroscience (R.G., A.V.), A. Meyer Children's Hospital, University of Florence; IRCCS Istituto Giannina Gaslini (M.I., P. Striano), Genova, Italy; Epilepsy Center Frankfurt Rhine-Main, Department of Neurology (K.M.K., P.S.R., F. Rosenow), University Hospital Frankfurt; LOEWE Center for Personalized Translational Epilepsy Research (CePTER) (K.M.K., P.S.R., F. Rosenow), Goethe-University Frankfurt, Germany; Departments of Clinical Neurosciences, Medical Genetics, and Community Health Sciences (K.M.K.), Hotchkiss Brain Institute & Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Canada; Department of Neurobiology and Epilepsy Center (I.K., S.S.P.), The Cyprus Institute of Neurology and Genetics, Nicosia; Institute of Experimental Epileptology and Cognition Research and Department of Epileptology (W.S.K.), University of Bonn, Germany; Division of Medical Genetics, Department of Pediatrics (M.M., S.M.), Duke University, Durham, NC; CeGaT GmbH and Praxis für Humangenetik Tübingen (L.M.), Germany; Division Biomedical Genetics (R.O.), University Medical Center Utrecht, the Netherlands; The Genomic Unit, Sheba Cancer Research Center (B.O.), Cancer Research Center, Wohl Institute for Translational Medicine (B.O.), and The Institute for Rare Diseases, The Edmond and Lily Safra Children's Hospital (A.R.), Sheba Medical Center, Tel Hashomer, Israel; Medical School (S.S.P.), University of Nicosia, Cyprus; Department of Pediatric Neuroscience (F. Ragona, T.G.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Member of the ERN EpiCARE, Milan, Italy; Sheba Medical Center, Tel-Hashomer; Sackler Faculty of Medicine (A.R.), Tel Aviv University, Israel; Departments of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health (P. Scudieri, P. Striano, F. Zara), University of Genova, Italy; Clinical Genetics and Genomics Department (G.A.T.), The Cyprus Institute of Neurology and Genetics, Nicosia; Department of Neurology (F. Zahnert), Epilepsy Center Hessen, Philipps-University Marburg, Germany; Division of Neurology (E.M.G., I.H.), The Epilepsy NeuroGenetics Initiative (ENGIN) (E.M.G., I.H.), and Department of Biomedical and Health Informatics (DBHi) (I.H.), Children's Hospital of Philadelphia, PA; Epilepsy Center, Neurological Institute (D.L.), and Genomic Medicine Institute, Lerner Research Institute (D.L.), Cleveland Clinic, OH; Stanley Center for Psychiatric Research (D.L.), The Broad Institute of Harvard and MIT, Cambridge, MA; Analytic and Translational Genetics Unit (D.L.), Massachusetts General Hospital, Boston; Luxembourg Centre for Systems Biomedicine (P.M.), University Luxembourg; Department of Neurology (I.H.), Perelman School of Medicine, University of Pennsylvania, PA; and Department of Epileptology and Neurology (Y.W.), University of Aachen, Germany.
Neurology. 2022 May 17;98(20):e2046-e2059. doi: 10.1212/WNL.0000000000200660. Epub 2022 Mar 21.
encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.
Individuals with variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in oocytes.
We identified novel variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms.
These findings implicate as a novel causative gene for epilepsy and emphasize the critical role of K3.2 in the regulation of brain excitability.
编码 Kv3.2，Shaw 相关（Kv3）电压门控钾通道亚家族的一员，对于大脑中持续的高频放电和动作电位的优化能量效率非常重要。本研究的目的是分析与疾病相关的 Kv3.2 变异体的临床表型、遗传背景和生物物理功能。
通过外显子组测序检测到的个体被选择进行临床、进一步的遗传和功能分析。病例是通过临床和研究合作转介的。选择新生变异体在卵母细胞中进行电生理检查。
我们在 18 名患有各种形式癫痫的患者中发现了新的 变异体，包括遗传性全面性癫痫（GGE）、发育性和癫痫性脑病（DEE），包括早发性失神癫痫、局灶性癫痫和肌阵挛性癫痫。在 18 个变异体中，有 10 个是新生的，8 个被归类为修饰变异体。8 名药物反应性患者使用丙戊酸单药或联合治疗成为无癫痫发作患者，包括严重的 DEE 病例。对 4 个变异体的功能分析表明，3 个严重 DEE 病例存在功能获得，1 个表型较轻（GGE）的病例存在功能丧失，这是潜在的病理机制。
这些发现提示 是癫痫的一个新的致病基因，并强调了 K3.2 在调节大脑兴奋性中的关键作用。
Zotero 插件
