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Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia

Journal of Human Genetics volume 65, pages 363–369 (2020)Cite this article

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Abstract

Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease characterized by cerebellar ataxia. Many causative genes have been identified to date, the most common etiology being the abnormal expansion of repeat sequences, and the mutation of ion channel genes also play an important role in the development of SCA. Some of them encode calcium and potassium channels. However, due to limited reports about potassium genes in SCA, we screened 192 Japanese individuals with dominantly inherited SCA who had no abnormal repeat expansions of causative genes for potassium channel mutations (KCNC3 for SCA13 and KCND3 for SCA19/SCA22) by target sequencing. As a result, two variants were identified from two patients: c.1973G>A, p.R658Q and c.1018G>A, p.V340M for KCNC3, and no pathogenic variant was identified for KCND3. The newly identified p.V340M exists in the extracellular domain, and p.R658Q exists in the intracellular domain on the C-terminal side, although most of the reported KCNC3 mutations are present at the transmembrane site. Adult-onset and slowly progressive cerebellar ataxia are the main clinical features of SCA13 and SCA19 caused by potassium channel mutations, which was similar in our cases. SCA13 caused by KCNC3 mutations may present with deep sensory loss and cognitive impairment in addition to cerebellar ataxia. In this study, mild deep sensory loss was observed in one case. SCA caused by potassium channel gene mutations is extremely rare, and more cases should be accumulated in the future to elucidate its pathogenesis due to channel dysfunction.

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Acknowledgements

We thank the families involved in this research, and Ms Mayumi Miyamoto and Ms Eiko Nakajima for their technical assistance. This study was partially supported by Takada Science Foundation and Uehara Memorial Foundation.

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Authors and Affiliations

  1. Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Yui Tada, Kodai Kume, Yukiko Matsuda, Yuhei Kanaya, Ryosuke Ohsawa, Hiroyuki Morino & Hideshi Kawakami

  2. Laboratory of Functional Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

    Yui Tada & Akira Kakizuka

  3. Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan

    Takashi Kurashige

  4. Department of Neurology, Kitano Hospital, Osaka, Japan

    Hayato Tabu

  5. Department of Neurology, Kansai Medical University, Osaka, Japan

    Satoshi Kaneko

  6. Department of Neurology, Tenri Hospital, Tenri, Japan

    Toshihiko Suenaga

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  1. Yui Tada
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Correspondence to Hideshi Kawakami.

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Tada, Y., Kume, K., Matsuda, Y. et al. Genetic screening for potassium channel mutations in Japanese autosomal dominant spinocerebellar ataxia. J Hum Genet 65, 363–369 (2020). https://doi.org/10.1038/s10038-019-0717-y

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