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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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References

  1. Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Prim. 2019;5:24.

    Article  Google Scholar 

  2. Zhuchenko O, Bailey J, Bonnen P, Ashizawa T, Stockton DW, Amos C, et al. Autosomal dominant cerebellar ataxia (SCA6) associated with small polyglutamine expansions in the alpha 1A-voltage-dependent calcium channel. Nat Genet. 1997;15:62–9.

    Article  CAS  Google Scholar 

  3. Coutelier M, Blesneac I, Monteil A, Monin ML, Ando K, Mundwiller E, et al. A recurrent mutation in CACNA1G alters Cav3.1 T-type calcium-channel conduction and causes autosomal-dominant cerebellar ataxia. Am J Hum Genet. 2015;97:726–37.

    Article  CAS  Google Scholar 

  4. Morino H, Matsuda Y, Muguruma K, Miyamoto R, Ohsawa R, Ohtake T, et al. A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Mol Brain. 2015;29:89.

    Article  CAS  Google Scholar 

  5. Kimura M, Yabe I, Hama Y, Eguchi K, Ura S, Tsuzaka K, et al. SCA42 mutation analysis in a case series of Japanese patients with spinocerebellar ataxia. J Hum Genet. 2017;62:857–9.

    Article  CAS  Google Scholar 

  6. Chemin J, Siquier-Pernet K, Nicouleau M, Barcia G, Ahmad A, Medina-Cano D, et al. De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. Brain. 2018;141:1998–2013.

    Article  Google Scholar 

  7. Waters MF, Minassian NA, Stevanin G, Figueroa KP, Bannister JP, Nolte D, et al. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet. 2006;38:447–51.

    Article  CAS  Google Scholar 

  8. Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, et al. Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19. Ann Neurol. 2012;72:870–80.

    Article  CAS  Google Scholar 

  9. Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, et al. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012;72:859–69.

    Article  CAS  Google Scholar 

  10. Subramony SH, Advincula J, Perlman S, Rosales RL, Lee LV, Ashizawa T. Comprehensive phenotype of the p.Arg420his allelic form of spinocerebellar ataxia type 13. Cerebellum. 2013;12:932–6.

    Article  CAS  Google Scholar 

  11. Pyle A, Smertenko T, Bargiela D, Griffin H, Duff J, Appleton M, et al. Exome sequencing in undiagnosed inherited and sporadic ataxias. Brain. 2015;138:276–83.

    Article  Google Scholar 

  12. Parolin Schnekenberg R, Perkins EM, Miller JW, Davies WI, D'Adamo MC, Pessia M, et al. De novo point mutations in patients diagnosed with ataxic cerebral palsy. Brain. 2015;138:1817–32.

    Article  Google Scholar 

  13. Montaut S, Apartis E, Chanson JB, Ewenczyk C, Renaud M, Guissart C, et al. SCA13 causes dominantly inherited non-progressive myoclonus ataxia. Parkinsonism Relat Disord. 2017;38:80–4.

    Article  Google Scholar 

  14. Huin V, Strubi-Vuillaume I, Dujardin K, Brion M, Delliaux M, Dellacherie D, et al. Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy. Parkinsonism Relat Disord. 2017;45:85–9.

    Article  Google Scholar 

  15. Khare S, Galeano K, Zhang Y, Nick JA, Nick HS, Subramony SH, et al. C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity. Cerebellum. 2018;17:692–7.

    Article  CAS  Google Scholar 

  16. Kurihara M, Ishiura H, Sasaki T, Otsuka J, Hayashi T, Terao Y, et al. Novel De Novo KCND3 mutation in a Japanese patient with intellectual disability, cerebellar ataxia, myoclonus, and dystonia. Cerebellum. 2018;17:237–42.

    Article  CAS  Google Scholar 

  17. Hsiao CT, Fu SJ, Liu YT, Lu YH, Zhong CY, Tang CY, et al. Novel SCA19/22-associated KCND3 mutations disrupt human K(V) 4.3 protein biosynthesis and channel gating. Hum Mutat. 2019;40:2088–107.

  18. Khare S, Nick JA, Zhang Y, Galeano K, Butler B, Khoshbouei H, et al. A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking. PLoS ONE. 2017;12:e0173565.

    Article  CAS  Google Scholar 

  19. Giudicessi JR, Ye D, Tester DJ, Crotti L, Mugione A, Nesterenko VV, et al. Transient outward current (Ito) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm. 2011;8:1024–32.

    Article  Google Scholar 

  20. Giudicessi JR, Ye D, Kritzberger CJ, Nesterenko VV, Tester DJ, Antzelevitch C, et al. Novel mutations in the KCND3‐encoded Kv4.3 K+ channel associated with autopsy‐negative sudden unexplained death. Hum Mutat. 2012;33:989–97.

    Article  CAS  Google Scholar 

  21. Seidel K, Küsters B, den Dunnen WF, Bouzrou M, Hageman G, Korf HW, et al. First patho-anatomical investigation of the brain of a SCA19 patient. Neuropathol Appl Neurobiol. 2014;40:640–4.

    Article  Google Scholar 

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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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