Novel SCA19/22-associated KCND3 mutations disrupt human KV4.3 protein biosynthesis and channel gating

Cheng Tsung Hsiao, Ssu Ju Fu, Yo Tsen Liu, Yi Hsiang Lu, Ciao Yu Zhong, Chih Yung Tang, Bing Wen Soong, Chung Jiuan Jeng

研究成果: 雜誌貢獻文章同行評審

6 引文 斯高帕斯(Scopus)


Mutations in the human voltage-gated K+ channel subunit KV4.3-encoding KCND3 gene have been associated with the autosomal dominant neurodegenerative disorder spinocerebellar ataxia types 19 and 22 (SCA19/22). The precise pathophysiology underlying the dominant inheritance pattern of SCA19/22 remains elusive. Using cerebellar ataxia-specific targeted next-generation sequencing technology, we identified two novel KCND3 mutations, c.950 G>A (p.C317Y) and c.1123 C>T (p.P375S) from a cohort with inherited cerebellar ataxias in Taiwan. The patients manifested notable phenotypic heterogeneity that includes cognitive impairment. We employed in vitro heterologous expression systems to inspect the biophysical and biochemical properties of human KV4.3 harboring the two novel mutations, as well as two previously reported but uncharacterized disease-related mutations, c.1013 T>A (p.V338E) and c.1130 C>T (p.T377M). Electrophysiological analyses revealed that all of these SCA19/22-associated KV4.3 mutant channels manifested loss-of-function phenotypes. Protein chemistry and immunofluorescence analyses further demonstrated that these mutants displayed enhanced protein degradation and defective membrane trafficking. By coexpressing KV4.3 wild-type with the disease-related mutants, we provided direct evidence showing that the mutants instigated anomalous protein biosynthesis and channel gating of KV4.3. We propose that the dominant inheritance pattern of SCA19/22 may be explained by the dominant-negative effects of the mutants on protein biosynthesis and voltage-dependent gating of KV4.3 wild-type channel.

頁(從 - 到)2088-2107
期刊Human Mutation
出版狀態已發佈 - 十一月 1 2019

ASJC Scopus subject areas

  • 遺傳學
  • 遺傳學(臨床)


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