دورية أكاديمية
أعرض في EDS

Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability.

التفاصيل البيبلوغرافية
العنوان: Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability.
المؤلفون: Wei AD; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington., Wakenight P; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington., Zwingman TA; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington., Bard AM; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington., Sahai N; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington., Willemsen MH; Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.; Department of Human Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands., Schelhaas HJ; Department of Neurology, Academic Centre for Epileptology Kempenhaeghe, Heeze, The Netherlands., Stegmann APA; Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands., Verhoeven JS; Department of Neurology, Academic Centre for Epileptology Kempenhaeghe, Heeze, The Netherlands., de Man SA; Department of Pediatrics, Amphia Hospital, Breda, The Netherlands.; Department of Human Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands., Wessels MW; Department of Human Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands., Kleefstra T; Department of Human Genetics and Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands., Shinde DN; Ambry Genetics, Aliso Viejo, California., Helbig KL; Ambry Genetics, Aliso Viejo, California.; Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania., Basinger A; Medical Genetics, Cook Children's Hospital, Fort Worth, Texas., Wagner VF; Department of Pediatrics, University of Texas Health Science Center, Houston, Texas., Rodriguez-Buritica D; Department of Pediatrics, University of Texas Health Science Center, Houston, Texas., Bryant E; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Millichap JJ; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.; Epilepsy Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois., Millen KJ; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington., Dobyns WB; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.; Department of Neurology, University of Washington School of Medicine, Seattle, Washington., Ramirez JM; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.; Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington., Kalume FK; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.; Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington.
المصدر: Journal of neurophysiology [J Neurophysiol] 2022 Jul 01; Vol. 128 (1), pp. 40-61. Date of Electronic Publication: 2022 May 18.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Physiological Society Country of Publication: United States NLM ID: 0375404 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1598 (Electronic) Linking ISSN: 00223077 NLM ISO Abbreviation: J Neurophysiol Subsets: MEDLINE
أسماء مطبوعة: Publication: Bethesda Md : American Physiological Society
Original Publication: Washington [etc.]
مواضيع طبية MeSH: Epilepsy*/genetics , Intellectual Disability*/genetics, Animals ; Child ; Cricetinae ; Cricetulus ; HEK293 Cells ; Humans ; KCNQ Potassium Channels ; Mice ; Mutation, Missense ; Seizures
مستخلص: We identified six novel de novo human KCNQ5 variants in children with motor/language delay, intellectual disability (ID), and/or epilepsy by whole exome sequencing. These variants, comprising two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported KCNQ5 missense variants (Lehman A, Thouta S, Mancini GM, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R; CAUSES Study; EPGEN Study; Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. Am J Hum Genet 101: 65-74, 2017). Surprisingly, all eight missense variants resulted in gain of function (GOF) due to hyperpolarized voltage dependence of activation or slowed deactivation kinetics, whereas the two nonsense variants were confirmed to be loss of function (LOF). One severe GOF allele ( P369T ) was tested and found to extend a dominant GOF effect to heteromeric KCNQ5/3 channels. Clinical presentations were associated with altered KCNQ5 channel gating: milder presentations with LOF or smaller GOF shifts in voltage dependence [change in voltage at half-maximal conduction (Δ V 50 ) = ∼-15 mV] and severe presentations with larger GOF shifts in voltage dependence (Δ V 50 = ∼-30 mV). To examine LOF pathogenicity, two Kcnq5 LOF mouse lines were created with CRISPR/Cas9. Both lines exhibited handling- and thermal-induced seizures and abnormal cortical EEGs consistent with epileptiform activity. Our study thus provides evidence for in vivo KCNQ5 LOF pathogenicity and strengthens the contribution of both LOF and GOF mutations to global pediatric neurological impairment, including ID/epilepsy. NEW & NOTEWORTHY Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental delay, intellectual disability, and/or epilepsy. Expression of these variants along with four previously reported KCNQ5 variants from a similar cohort revealed GOF potassium channels, negatively shifted in V 50 of activation and/or delayed deactivation kinetics. GOF is extended to KCNQ5/3 heteromeric channels, making these the predominant channels affected in heterozygous de novo patients. Kcnq5 LOF mice exhibited seizures, consistent with in vivo pathogenicity.
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معلومات مُعتمدة: R01 HL126523 United States HL NHLBI NIH HHS; R01 NS092772 United States NS NINDS NIH HHS; P50 HD103524 United States HD NICHD NIH HHS; R01 NS102796 United States NS NINDS NIH HHS; R01 NS099027 United States NS NINDS NIH HHS; R01 NS095733 United States NS NINDS NIH HHS
فهرسة مساهمة: Keywords: KCNQ5; M current; channelopathy; epilepsy; intellectual disability
المشرفين على المادة: 0 (KCNQ Potassium Channels)
0 (KCNQ5 protein, human)
تواريخ الأحداث: Date Created: 20220518 Date Completed: 20220629 Latest Revision: 20230703
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC9236882
DOI: 10.1152/jn.00509.2021
PMID: 35583973
قاعدة البيانات: MEDLINE
الوصف
تدمد:1522-1598
DOI:10.1152/jn.00509.2021