Frontiers in Molecular Neuroscience (Jun 2022)
Rare KCND3 Loss-of-Function Mutation Associated With the SCA19/22
- Mengjie Li,
- Fen Liu,
- Fen Liu,
- Xiaoyan Hao,
- Xiaoyan Hao,
- Yu Fan,
- Yu Fan,
- Jiadi Li,
- Jiadi Li,
- Zhengwei Hu,
- Zhengwei Hu,
- Jingjing Shi,
- Jingjing Shi,
- Liyuan Fan,
- Liyuan Fan,
- Shuo Zhang,
- Shuo Zhang,
- Dongrui Ma,
- Mengnan Guo,
- Yuming Xu,
- Yuming Xu,
- Yuming Xu,
- Yuming Xu,
- Yuming Xu,
- Yuming Xu,
- Changhe Shi,
- Changhe Shi,
- Changhe Shi,
- Changhe Shi,
- Changhe Shi
Affiliations
- Mengjie Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Fen Liu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Fen Liu
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Xiaoyan Hao
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Xiaoyan Hao
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Yu Fan
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Yu Fan
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Jiadi Li
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Jiadi Li
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Zhengwei Hu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Zhengwei Hu
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Jingjing Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Jingjing Shi
- Department of Cell Biology and Medical Genetics, Basic Medical College of Zhengzhou University, Zhengzhou, China
- Liyuan Fan
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Liyuan Fan
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Shuo Zhang
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Shuo Zhang
- Academy of Medical Sciences of Zhengzhou University, Zhengzhou, China
- Dongrui Ma
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Mengnan Guo
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Yuming Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Yuming Xu
- Department of Cell Biology and Medical Genetics, Basic Medical College of Zhengzhou University, Zhengzhou, China
- Yuming Xu
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Yuming Xu
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Yuming Xu
- The Henan Medical Key Laboratory of Hereditary Neurodegenerative Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Yuming Xu
- The Key Laboratory of Cerebrovascular Diseases Prevention and Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Changhe Shi
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Changhe Shi
- Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Changhe Shi
- Institute of Neuroscience, Zhengzhou University, Zhengzhou, China
- Changhe Shi
- The Henan Medical Key Laboratory of Hereditary Neurodegenerative Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- Changhe Shi
- The Key Laboratory of Cerebrovascular Diseases Prevention and Treatment, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China
- DOI
- https://doi.org/10.3389/fnmol.2022.919199
- Journal volume & issue
-
Vol. 15
Abstract
Spinocerebellar ataxia 19/22 (SCA19/22) is a rare neurodegenerative disorder caused by mutations of the KCND3 gene, which encodes the Kv4. 3 protein. Currently, only 22 KCND3 single-nucleotide mutation sites of SCA19/22 have been reported worldwide, and detailed pathogenesis remains unclear. In this study, Sanger sequencing was used to screen 115 probands of cerebellar ataxia families in 67 patients with sporadic cerebellar ataxia and 200 healthy people to identify KCND3 mutations. Mutant gene products showed pathogenicity damage, and the polarity was changed. Next, we established induced pluripotent stem cells (iPSCs) derived from SCA19/22 patients. Using a transcriptome sequencing technique, we found that protein processing in the endoplasmic reticulum was significantly enriched in SCA19/22-iPS-derived neurons and was closely related to endoplasmic reticulum stress (ERS) and apoptosis. In addition, Western blotting of the SCA19/22-iPS-derived neurons showed a reduction in Kv4.3; but, activation of transcription factor 4 (ATF4) and C/EBP homologous protein was increased. Therefore, the c.1130 C>T (p.T377M) mutation of the KCND3 gene may mediate misfold and aggregation of Kv4.3, which activates the ERS and further induces neuron apoptosis involved in SCA19/22.
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