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Mol Brain. 2015 Dec 29;8:89. doi: 10.1186/s13041-015-0180-4.

A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia.

Author information

1
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. morino@hiroshima-u.ac.jp.
2
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. yoshimot@hiroshima-u.ac.jp.
3
Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe, Japan. muguruma@cdb.riken.jp.
4
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. rmiyamoto@clin.med.tokushima-u.ac.jp.
5
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. rohsawa@hiroshima-u.ac.jp.
6
Department of Neurology, Tokyo Metropolitan Health and Medical Treatment Corporation Ebara Hospital, Tokyo, Japan. toshiyuki_ohtake@tokyo-hmt.jp.
7
Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan. reiko0261@hiroshima-u.ac.jp.
8
Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan. watamasa@med.hokudai.ac.jp.
9
Department of Clinical Neuroscience & Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. hmaru@hiroshima-u.ac.jp.
10
Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. hashik@hiroshima-u.ac.jp.
11
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. hkawakam@hiroshima-u.ac.jp.

Abstract

BACKGROUND:

Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease. To date, 36 dominantly inherited loci have been reported, and 31 causative genes have been identified.

RESULTS:

In this study, we analyzed a Japanese family with autosomal dominant SCA using linkage analysis and exome sequencing, and identified CACNA1G, which encodes the calcium channel CaV3.1, as a new causative gene. The same mutation was also found in another family with SCA. Although most patients exhibited the pure form of cerebellar ataxia, two patients showed prominent resting tremor in addition to ataxia. CaV3.1 is classified as a low-threshold voltage-dependent calcium channel (T-type) and is expressed abundantly in the central nervous system, including the cerebellum. The mutation p.Arg1715His, identified in this study, was found to be located at S4 of repeat IV, the voltage sensor of the CaV3.1. Electrophysiological analyses revealed that the membrane potential dependency of the mutant CaV3.1 transfected into HEK293T cells shifted toward a positive potential. We established induced pluripotent stem cells (iPSCs) from fibroblasts of the patient, and to our knowledge, this is the first report of successful differentiation from the patient-derived iPSCs into Purkinje cells. There was no significant difference in the differentiation status between control- and patient-derived iPSCs.

CONCLUSIONS:

To date, several channel genes have been reported as causative genes for SCA. Our findings provide important insights into the pathogenesis of SCA as a channelopathy.

PMID:
26715324
PMCID:
PMC4693440
DOI:
10.1186/s13041-015-0180-4
[Indexed for MEDLINE]
Free PMC Article

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