Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency

• Published in: Annals of neurology Vol. 96; no. 4; pp. 758 - 773
• Main Authors: Li, Yun‐Lu, Lin, Jingjing, Huang, Xuejing, Zeng, Rui‐Huang, Zhang, Guangyu, Xu, Jie‐Ni, Lin, Kai‐Jun, Chen, Xin‐Shuo, He, Ming‐Feng, Qiao, Jing‐Da, Cheng, Xuewen, Zhu, Dengna, Xiong, Zhi‐Qi, Chen, Wan‐Jin
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.10.2024; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Animals; Cell migration; Child; Complementation; Drosophila; Drosophila - genetics; Dyskinesia; Dystonia; Dystonia - genetics; Excitability; Exome Sequencing; Female; Fruit flies; Gene sequencing; Genetic diversity; Genetic variance; Haploinsufficiency; Haploinsufficiency - genetics; HEK293 Cells; Heterozygote; Homozygotes; Humans; Insects; Male; Mutation - genetics; Neuronal-glial interactions; Paroxysmal kinesigenic dyskinesia; Pathogenesis; Patients; Pedigree; Phenotypes; Potassium channels (inwardly-rectifying); Potassium Channels, Inwardly Rectifying - genetics; Potassium currents; Whole genome sequencing; Young Adult
• DOI: 10.1002/ana.27018
• ISSN: 0364-5134; 1531-8249

Objective Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients. Methods Whole‐exome sequencing was performed for 106 PRRT2‐negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila. Results Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2‐negative probands. Both co‐segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation‐carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch‐clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient‐derived variants, indicating a loss‐of‐function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock‐in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia‐specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes. Interpretation Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024;96:758–773