Heterozygous KCNJ10 Variants Affecting Kir4.1 Channel Cause Paroxysmal Kinesigenic Dyskinesia.

Autor:	Huang X; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China., Fu X; Center for Brain Science, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wu J; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China., Cheng X; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China., Hong X; Department of Obstetrics and Gynecology, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Li Z; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China., Zheng L; Department of Neurology, Minhang Hospital, Fudan University, Shanghai, China., Liu Q; Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China., Chen S; Department of Neurology and Institute of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Tang B; Department of Neurology, Xiangya Hospital, Central South University, Changsha, China., Zhao Y; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China., Liu X; Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China., Li X; Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China., Liu X; Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai, China., Zhou Z; Shanghai Xunyin Biotechnology Co., Ltd., Shanghai, China., Wu L; Department of Neurology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Fang K; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhong P; Department of Neurology, Suzhou Hospital of Anhui Medical University, HeFei, China., Zhang M; Department of Neurology, The First Hospital Affiliated to Anhui University of Science and Technology, HeFei, China., Luan X; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China., Tian W; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China., Tong X; Department of Obstetrics and Gynecology, Songjiang Hospital and Songjiang Research Institute, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Cao L; Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Neurological Rare Disease Biobank and Precision Diagnostic Technical Service Platform, Shanghai, China.; Department of Neurology, Suzhou Hospital of Anhui Medical University, HeFei, China.; Department of Neurology, The First Hospital Affiliated to Anhui University of Science and Technology, HeFei, China.
Jazyk:	angličtina
Zdroj:	Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2024 Oct 05. Date of Electronic Publication: 2024 Oct 05.
DOI:	10.1002/mds.30025
Abstrakt:	Background: More than 60% of paroxysmal kinesigenic dyskinesia (PKD) cases are of uncertain variants. Objective: The aim was to elucidate novel genetic contribution to PKD. Methods: A total of 476 probands with uncertain genetic causes were enrolled for whole-exome sequencing. A method of case-control analysis was applied to identify the candidate genes. Whole-cell patch-clamp recording was applied to verify the electrophysiological impact of the identified variants. A mouse model with cerebellar heterozygous knockout of the candidate gene was developed via adeno-associated virus injection, and dystonia-like phenotype inducement and rotarod tests were performed. In vivo multiunit electrical recording was applied to investigate the change in neural excitability in knockout mice. Results: Heterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) clustered in PKD patients were compared with those in the control groups. Fifteen variants were detected in 16 of 522 probands (frequency = 3.07%). Patients with KCNJ10 variants tended to have a milder manifestation compared to those with PRRT2 (proline-rich transmembrane protein 2) variants. KCNJ10 variants partially altered the transmembrane location of inwardly rectifying potassium channel 4.1 (Kir4.1). The Kcnj10 expression is consistent with the natural course of PKD. Variants resulted in different degrees of reduction in cell Kir4.1 currents, and mice with heterozygous conditional knockout of Kcnj10 in the cerebellum presented dystonic posture, together with poor motor coordination and motor learning ability in rotarod tests. The firing rate of deep cerebellar nuclei was significantly elevated in Kcnj10-cKO mice. Conclusion: We identified heterozygous variants of KCNJ10 in PKD. Impaired function of Kir4.1 might lead to abnormal neuronal excitability, which attributed to PKD. © 2024 International Parkinson and Movement Disorder Society. (© 2024 International Parkinson and Movement Disorder Society.)
Databáze:	MEDLINE
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