title: A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.
abstract: 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.
authors.affiliation: INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium; Ecole Pratique des Hautes Etudes, 75014 Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Coutelier
authors.affiliation: Centre National de la Recherche Scientifique UMR 5203 and INSERM U 1191, Institut de Génomique Fonctionnelle, Université de Montpellier, 34094 Montpellier, France; LabEx "Ion Channel Science and Therapeutics," 34094 Montpellier, France.
authors.forename: Iulia
authors.initials: I
authors.lastname: Blesneac
authors.affiliation: Centre National de la Recherche Scientifique UMR 5203 and INSERM U 1191, Institut de Génomique Fonctionnelle, Université de Montpellier, 34094 Montpellier, France; LabEx "Ion Channel Science and Therapeutics," 34094 Montpellier, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Monteil
authors.affiliation: INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
authors.forename: Marie-Lorraine
authors.initials: ML
authors.lastname: Monin
authors.affiliation: INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Laboratoire de Neuropathologie Escourolle, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Kunie
authors.initials: K
authors.lastname: Ando
authors.affiliation: Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.
authors.forename: Emeline
authors.initials: E
authors.lastname: Mundwiller
authors.affiliation: Department of Medical Sciences, University of Turin, 10126 Turin, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, 10126 Turin, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Brusco
authors.affiliation: INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Fédération des Maladies du Système Nerveux, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Le Ber
authors.affiliation: Département de Neurologie, Hôpital de Hautepierre, Centre Hospitalier Universitaire de Strasbourg, 67098 Strasbourg, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM U 964, Centre National de la Recherche Scientifique UMR 7104, Université de Strasbourg, 67400 Illkirch, France; Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, 67081 Strasbourg, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Anheim
authors.affiliation: Unité Troubles du Mouvement, Pôle de Neurologie et Psychiatrie, Centre Hospitalier Universitaire de Grenoble, 38700 Grenoble, France; Equipe Fonctions Cérébrales et Neuromodulation, Grenoble Institut des Neurosciences, INSERM U 836, Université Joseph Fourier, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Centre Hospitalier Universitaire de Grenoble, 38700 Grenoble, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Castrioto
authors.affiliation: INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Laboratoire de Neuropathologie Escourolle, Hôpital de la Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.affiliation: INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: Centre National de la Recherche Scientifique UMR 5203 and INSERM U 1191, Institut de Génomique Fonctionnelle, Université de Montpellier, 34094 Montpellier, France; LabEx "Ion Channel Science and Therapeutics," 34094 Montpellier, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lory
authors.affiliation: INSERM U 1127, 75013 Paris, France; Centre National de la Recherche Scientifique UMR 7225, 75013 Paris, France; UMRS 1127, Université Pierre et Marie Curie (Paris 06), Sorbonne Universités, 75013 Paris, France; Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France; Ecole Pratique des Hautes Etudes, 75014 Paris, France; Centre de Référence de Neurogénétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France. Electronic address: giovanni.stevanin@upmc.fr.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002648:Child; D004594:Electrophysiology; D005260:Female; D005799:Genes, Dominant; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010375:Pedigree; D010641:Phenotype; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: C121855:CACNA1G protein, human; D020747:Calcium Channels, T-Type; D002118:Calcium