Rare gain-of-function kcnd3 variant associated with cerebellar ataxia, parkinsonism, cognitive dysfunction, and brain iron accumulation

Cheng Tsung Hsiao, Thomas F. Tropea, Ssu Ju Fu, Tanya M. Bardakjian, Pedro Gonzalez-Alegre, Bing Wen Soong, Chih Yung Tang*, Chung Jiuan Jeng

*此作品的通信作者

研究成果: Article同行評審

1 引文 斯高帕斯(Scopus)

摘要

Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neu-rodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of KCND3 variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cere-bellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous KCND3 c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human KV4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the KV4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function KCND3 mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function KCND3 variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation.

原文English
文章編號8247
期刊International Journal Of Molecular Sciences
22
發行號15
DOIs
出版狀態Published - 1 8月 2021

指紋

深入研究「Rare gain-of-function kcnd3 variant associated with cerebellar ataxia, parkinsonism, cognitive dysfunction, and brain iron accumulation」主題。共同形成了獨特的指紋。

引用此