Novel SCA19/22‐associated KCND3 mutations disrupt human K V 4.3 protein biosynthesis and channel gating
| العنوان: | Novel SCA19/22‐associated KCND3 mutations disrupt human K V 4.3 protein biosynthesis and channel gating |
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| المؤلفون: | Bing-Wen Soong, Ssu Ju Fu, Yo Tsen Liu, Ciao Yu Zhong, Chung Jiuan Jeng, Cheng Tsung Hsiao, Chih Yung Tang, Yi Hsiang Lu |
| المصدر: | Human Mutation. 40:2088-2107 |
| بيانات النشر: | Hindawi Limited, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0303 health sciences, Protein subunit, 030305 genetics & heredity, Mutant, Gating, Protein degradation, Biology, medicine.disease, Phenotype, Cell biology, 03 medical and health sciences, Genetics, Spinocerebellar ataxia, medicine, Protein biosynthesis, Gene, Genetics (clinical), 030304 developmental biology |
| الوصف: | Mutations in the human voltage-gated K+ channel subunit KV 4.3-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 KV 4.3 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 KV 4.3 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 KV 4.3 wild-type with the disease-related mutants, we provided direct evidence showing that the mutants instigated anomalous protein biosynthesis and channel gating of KV 4.3. 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 KV 4.3 wild-type channel. |
| تدمد: | 1098-1004 1059-7794 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::4b249f1cbe6addaf077d48b707eb547c https://doi.org/10.1002/humu.23865 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi...........4b249f1cbe6addaf077d48b707eb547c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10981004 10597794 |
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