BackgroundSpinocerebellar ataxia (SCA) is a genetically heterogeneous disease. To date, 36 dominantly inherited loci have been reported, and 31 causative genes have been identified.ResultsIn 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.ConclusionsTo 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0180-4) contains supplementary material, which is available to authorized users.
Background: A missense mutation of the THAP1 gene results in DYT6 primary dystonia. While deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in treating primary dystonia, recent reports indicate that GPi DBS is only mildly effective for DYT6 dystonia. Objective: To describe a patient with DYT6 dystonia who underwent thalamic ventral lateral anterior (VLa) nucleus DBS. Patient: A 35-year-old Japanese man had been experiencing upper limb dystonia and spasmodic dysphonia since the age of 15. His dystonic symptoms progressed to generalized dystonia. He was diagnosed as having DYT6 dystonia with mutations in the THAP1 gene. Because his dystonic symptoms were refractory to pharmacotherapy and pallidal DBS, he underwent thalamic VLa DBS. Results: Continuous bilateral VLa stimulation with optimal parameter settings ameliorated the patient's dystonic symptoms. At the 2-year follow-up, his Burke-Fahn-Marsden Dystonia Rating Scale total score decreased from 71 to 11, an improvement of more than 80%. Conclusions: The thalamic VLa nucleus could serve as an alternative target in DBS therapy for DYT6 dystonia.
Extracerebellar symptoms may be seen in most cases of both autosomal dominant and recessive cerebellar ataxias, being characterized by multisystem involvement. 1 Autosomal re-cessive spinocerebellar ataxia type 16 (SCAR16) is an adolescent-onset ataxia with cerebellar atrophy, occasionally accompanied by cognitive decline, spasticity, hypogonadism, and movement disorders. 2 In 2013, the STIP1 homologous and U Box-containing protein 1 gene (STUB1; 16p13.3; OMIM: *607207), was identified as a novel causative gene for SCAR16, which encodes the C-terminus of the heat shock protein 70interacting protein, 3 which has a biological role in regulating Figure.
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