KCNT2-Related Disorders: Phenotypes, Functional, and Pharmacological Properties.

Autor: Cioclu MC; Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark.; Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, Modena, Italy., Mosca I; Department of Medicine and Health Sciences 'Vincenzo Tiberio', University of Molise, Campobasso, Italy., Ambrosino P; Dept. of Science and Technology, University of Sannio, Benevento, Italy., Puzo D; Department of Medicine and Health Sciences 'Vincenzo Tiberio', University of Molise, Campobasso, Italy., Bayat A; Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark.; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark., Wortmann SB; University Children's Hospital, Paracelsus Medical University, Salzburg, Austria.; Amalia Children's Hospital, Nijmegen, The Netherlands., Koch J; University Children's Hospital, Paracelsus Medical University, Salzburg, Austria., Strehlow V; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Shirai K; Department of Pediatrics, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan., Matsumoto N; Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan., Sanders SJ; Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.; Institute for Human Genetics, University of California, San Francisco, CA, USA.; Bakar Computational Health Sciences Institute, University of California, San Francisco, CA, USA., Michaud V; Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.; Maladies rares: Génétique et Métabolisme (MRGM), INSERM U1211, Université de Bordeaux, Bordeaux, France., Legendre M; Service de Génétique Médicale, Centre de Référence Anomalies du Développement et Syndrome Malformatifs, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France., Riva A; IRCCS Istituto Giannina Gaslini, Genoa, Italy.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy., Striano P; IRCCS Istituto Giannina Gaslini, Genoa, Italy.; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy., Muhle H; Department of Neuropediatrics, University Medical Centre Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany., Pendziwiat M; Department of Neuropediatrics, University Medical Centre Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany., Lesca G; Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261-INSERM U1315, Lyon, France.; Department of Medical Genetics, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France., Mangano GD; Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy., Nardello R; Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties 'G. D'Alessandro', University of Palermo, Palermo, Italy., Lemke JR; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany., Møller RS; Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark.; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark., Soldovieri MV; Department of Medicine and Health Sciences 'Vincenzo Tiberio', University of Molise, Campobasso, Italy., Rubboli G; Department of Epilepsy Genetics and Personalized Medicine (member of ERN EpiCARE), Danish Epilepsy Centre, Dianalund, Denmark.; University of Copenhagen, Copenhagen, Denmark., Taglialatela M; Department of Neuroscience, University of Naples 'Federico II', Naples, Italy.
Jazyk: angličtina
Zdroj: Annals of neurology [Ann Neurol] 2023 Aug; Vol. 94 (2), pp. 332-349. Date of Electronic Publication: 2023 May 22.
DOI: 10.1002/ana.26662
Abstrakt: Objective: Pathogenic variants in KCNT2 are rare causes of developmental epileptic encephalopathy (DEE). We herein describe the phenotypic and genetic features of patients with KCNT2-related DEE, and the in vitro functional and pharmacological properties of KCNT2 channels carrying 14 novel or previously untested variants.
Methods: Twenty-five patients harboring KCNT2 variants were investigated: 12 were identified through an international collaborative network, 13 were retrieved from the literature. Clinical data were collected and included in a standardized phenotyping sheet. Novel variants were detected using exome sequencing and classified using ACMG criteria. Functional and pharmacological studies were performed by whole-cell electrophysiology in HEK-293 and SH-SY5Y cells.
Results: The phenotypic spectrum encompassed: (a) intellectual disability/developmental delay (21/22 individuals with available information), ranging from mild to severe/profound; (b) epilepsy (15/25); (c) neurological impairment, with altered muscle tone (14/22); (d) dysmorphisms (13/20). Nineteen pathogenic KCNT2 variants were found (9 new, 10 reported previously): 16 missense, 1 in-frame deletion of a single amino acid, 1 nonsense, and 1 frameshift. Among tested variants, 8 showed gain-of-function (GoF), and 6 loss-of-function (LoF) features when expressed heterologously in vitro. Quinidine and fluoxetine blocked all GoF variants, whereas loxapine and riluzole activated some LoF variants while blocking others.
Interpretation: We expanded the phenotypic and genotypic spectrum of KCNT2-related disorders, highlighting novel genotype-phenotype associations. Pathogenic KCNT2 variants cause GoF or LoF in vitro phenotypes, and each shows a unique pharmacological profile, suggesting the need for in vitro functional and pharmacological investigation to enable targeted therapies based on the molecular phenotype. ANN NEUROL 2023;94:332-349.
(© 2023 American Neurological Association.)
Databáze: MEDLINE
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