title: A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia.
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.
authors.affiliation: 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.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Morino
authors.affiliation: 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.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Matsuda
authors.affiliation: Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe, Japan. muguruma@cdb.riken.jp.
authors.forename: Keiko
authors.initials: K
authors.lastname: Muguruma
authors.affiliation: 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.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Miyamoto
authors.affiliation: 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.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Ohsawa
authors.affiliation: Department of Neurology, Tokyo Metropolitan Health and Medical Treatment Corporation Ebara Hospital, Tokyo, Japan. toshiyuki_ohtake@tokyo-hmt.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ohtake
authors.affiliation: Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan. reiko0261@hiroshima-u.ac.jp.
authors.forename: Reiko
authors.initials: R
authors.lastname: Otobe
authors.affiliation: Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan. watamasa@med.hokudai.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Clinical Neuroscience & Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. hmaru@hiroshima-u.ac.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. hashik@hiroshima-u.ac.jp.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: 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.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Kawakami
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D044466:Asian People / Q000235:genetics; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000502:physiology; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D005799:Genes, Dominant; D008040:Genetic Linkage; D005838:Genotype; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D007564:Japan; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D055495:Neurogenesis; D018408:Patch-Clamp Techniques; D010375:Pedigree; D011689:Purkinje Cells / Q000166:cytology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: C121855:CACNA1G protein, human; D020747:Calcium Channels, T-Type; D011993:Recombinant Fusion Proteins