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The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND
L. Qebibo, A. Davakan, M. Nesson-Dauphin, N. Boulali, K. Siquier-Pernet, A. Afenjar, J. Amiel, D. Bartholdi, M. Barth, E. Blondiaux, I. Cristian, Z. Frazier, A. Goldenberg, JM. Good, CL. Salussolia, M. Sahin, H. McCullagh, K. McDonald, A. McRae,...
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články
- MeSH
- dítě MeSH
- fenotyp * MeSH
- genetické asociační studie MeSH
- heterozygot MeSH
- kojenec MeSH
- lidé MeSH
- missense mutace * genetika MeSH
- mladiství MeSH
- neurovývojové poruchy * genetika patologie MeSH
- předškolní dítě MeSH
- vápníkové kanály - typ T * genetika metabolismus MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
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 an 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.
Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL
Arnold Palmer Hospital for Children Orlando Health FL
Charles University Motol University Hospital Prague Czech Republic
Department of Biochemistry and Genetics Angers University Hospital Angers France
Department of Human Genetics Inselspital Bern University Hospital University of Bern Switzerland
Department of Pediatrics University of Louisville Norton Children's Hospital Louisville KY
Department of Radiology Armand Trousseau Hospital APHP Sorbonne University Paris France
IGF Université de Montpellier CNRS INSERM Montpellier France
LabEx Ion Channel Science and Therapeutics Montpellier France
Leeds Teaching Hospitals NHS Trust Leeds United Kingdom
Tel Aviv Sourasky Medical Center Genetic Institute Tel Aviv Israel
Unité fonctionnelle de Génétique Médicale Centre Hospitalier Universitaire Tours France
Citace poskytuje Crossref.org
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- $a Qebibo, Leila $u Pediatric Neurogenetics Laboratory, Department of Genetics, Armand-Trousseau Hospital, AP-HP. 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, Paris, France
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- $a The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND / $c L. Qebibo, A. Davakan, M. Nesson-Dauphin, N. Boulali, K. Siquier-Pernet, A. Afenjar, J. Amiel, D. Bartholdi, M. Barth, E. Blondiaux, I. Cristian, Z. Frazier, A. Goldenberg, JM. Good, CL. Salussolia, M. Sahin, H. McCullagh, K. McDonald, A. McRae, J. Morrison, J. Pinner, M. Shinawi, A. Toutain, E. Vyhnálková, PG. Wheeler, Y. Wilnai, M. Hausman-Kedem, M. Coolen, V. Cantagrel, L. Burglen, P. Lory
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