The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND.

Autor:	Qebibo L; Pediatric Neurogenetics Laboratory, Department of Genetics, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France; Reference Center for Cerebellar Malformations and Congenital Diseases, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders, Laboratory, 75015, Paris, France., Davakan A; IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France; LabEx 'Ion Channel Science and Therapeutics', Montpellier, France., Nesson-Dauphin M; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders, Laboratory, 75015, Paris, France., Boulali N; IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France; LabEx 'Ion Channel Science and Therapeutics', Montpellier, France., Siquier-Pernet K; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders, Laboratory, 75015, Paris, France., Afenjar A; Reference Center for Cerebellar Malformations and Congenital Diseases, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France., Amiel J; Service de Médecine Génomique des Maladies Rares, Necker Enfants Malades University Hospital, APHP, Paris, France., Bartholdi D; Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Switzerland., Barth M; Department of Biochemistry and Genetics, Angers University Hospital, Angers, France., Blondiaux E; Department of Radiology, Armand-Trousseau Hospital, APHP, Sorbonne University, Paris, France., Cristian I; Arnold Palmer Hospital for Children, Orlando Health, Florida, USA., Frazier Z; Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, USA., Goldenberg A; Université Rouen Normandie, INSERM U1245, CHU de Rouen, Department of Genetics and Reference Center for Developmental Disorders, Rouen, France., Good JM; Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland., Salussolia CL; Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, USA., Sahin M; Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, USA., McCullagh H; Leeds Teaching Hospitals NHS Trust, Leeds, UK., McDonald K; Department of Pediatrics, University of Louisville, Norton Children's Hospital, Louisville, USA., McRae A; Ann & Robert H. Lurie Children's Hospital of Chicago, USA., Morrison J; Arnold Palmer Hospital for Children, Orlando Health, Florida, USA., Pinner J; Centre for Clinical Genetics, Sydney Children's Hospitals Network and University of New South Wales, Sydney, Australia., Shinawi M; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, USA., Toutain A; Unité fonctionnelle de Génétique Médicale, Centre Hospitalier Universitaire, 37044, Tours, France., Vyhnálková E; Charles University, Motol University Hospital, Prague, Czech Republic., Wheeler PG; Arnold Palmer Hospital for Children, Orlando Health, Florida, USA., Wilnai Y; Tel Aviv Sourasky Medical Center, Genetic Institute, Tel Aviv, Israel., Hausman-Kedem M; Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Medical Center and Faculty of Medical and Health Science, Tel-Aviv University, Tel-Aviv, Israel., Coolen M; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders, Laboratory, 75015, Paris, France., Cantagrel V; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders, Laboratory, 75015, Paris, France. Electronic address: vincent.cantagrel@inserm.fr., Burglen L; Pediatric Neurogenetics Laboratory, Department of Genetics, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France; Reference Center for Cerebellar Malformations and Congenital Diseases, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders, Laboratory, 75015, Paris, France. Electronic address: lydie.burglen@aphp.fr., Lory P; IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France; LabEx 'Ion Channel Science and Therapeutics', Montpellier, France. Electronic address: philippe.lory@igf.cnrs.fr.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 Dec 12, pp. 101337. Date of Electronic Publication: 2024 Dec 12.
DOI:	10.1016/j.gim.2024.101337
Abstrakt:	Purpose: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. Methods: We describe 19 patients with congenital CACNA1G-variants including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. Results: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics, and increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. Conclusion: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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