A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.
The American Journal of Human Genetics. 2015-11-01; 97(5): 726-737
DOI: 10.1016/j.ajhg.2015.09.007
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1. Am J Hum Genet. 2015 Nov 5;97(5):726-37. doi: 10.1016/j.ajhg.2015.09.007. Epub
2015 Oct 8.
A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction
and Causes Autosomal-Dominant Cerebellar Ataxia.
Coutelier M(1), Blesneac I(2), Monteil A(2), Monin ML(3), Ando K(4), Mundwiller
E(5), Brusco A(6), Le Ber I(7), Anheim M(8), Castrioto A(9), Duyckaerts C(4),
Brice A(3), Durr A(3), Lory P(2), Stevanin G(10).
Author information:
(1)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.
(2)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.
(3)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.
(4)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.
(5)Institut du Cerveau et de la Moelle Épinière, 75013 Paris, France.
(6)Department of Medical Sciences, University of Turin, 10126 Turin, Italy;
Medical Genetics Unit, Città della Salute e della Scienza University Hospital,
10126 Turin, Italy.
(7)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.
(8)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.
(9)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.
(10)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: .
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.
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.
DOI: 10.1016/j.ajhg.2015.09.007
PMCID: PMC4667105
PMID: 26456284 [Indexed for MEDLINE]