Academic Journal
A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia
| العنوان: | A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia |
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| المؤلفون: | Coutelier, Marie, Blesneac, Iulia, Monteil, Arnaud, Monin, Marie-Lorraine, Ando, Kunie, Mundwiller, Emeline, Brusco, Alfredo, Le ber, Isabelle, Anheim, Mathieu, Castrioto, Anna, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Lory, Philippe, Stevanin, Giovanni |
| المساهمون: | Laboratory of Human Molecular Genetics, Université Catholique de Louvain = Catholic University of Louvain (UCL)-de Duve Institute, École Pratique des Hautes Études (EPHE), Université Paris Sciences et Lettres (PSL), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), LabEx Ion Channel Science and Therapeutics, CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle CHU Pitié-Salpétriêre, Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Medical Sciences, Università degli studi di Torino = University of Turin (UNITO), Medical Genetics Unit, Città della Salute e della Scienza di Torino (A.O.U), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Département de Neurologie - Hôpital de Hautepierre, Unité Médicale des Troubles du Mouvement, Centre Hospitalier Universitaire CHU Grenoble (CHUGA)-Clinique de Neurologie, Fonctions cérébrales et neuromodulation, GIN Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA) |
| المصدر: | ISSN: 0002-9297. |
| بيانات النشر: | HAL CCSD Elsevier (Cell Press) |
| سنة النشر: | 2015 |
| المجموعة: | Université de Montpellier: HAL |
| مصطلحات موضوعية: | [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] |
| الوصف: | International audience ; Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | hal-01223815; https://hal.sorbonne-universite.fr/hal-01223815; https://hal.sorbonne-universite.fr/hal-01223815/document; https://hal.sorbonne-universite.fr/hal-01223815/file/Coutelier_A_Recurrent.pdf |
| DOI: | 10.1016/j.ajhg.2015.09.007 |
| الاتاحة: | https://hal.sorbonne-universite.fr/hal-01223815 https://hal.sorbonne-universite.fr/hal-01223815/document https://hal.sorbonne-universite.fr/hal-01223815/file/Coutelier_A_Recurrent.pdf https://doi.org/10.1016/j.ajhg.2015.09.007 |
| Rights: | info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.2F78C241 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ajhg.2015.09.007 |
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