Heterozygous Loss‐of‐Function Variants of KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia

2026/03/02 by Wan-Bing Sun, Wan‐Bing Sun, Jiao‐jiao Xu +11
Biochemistry, Genetics and Molecular Biology · Neuroscience · Medicine · #Genomics and Rare Diseases #Genetic Neurodegenerative Diseases #Parkinson's Disease Mechanisms and Treatments

paper · doi:10.1002/mds.70247

Abstract

BACKGROUND: Heterozygous variants of potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) were previously reported to be enriched in several patients with paroxysmal kinesigenic dyskinesia (PKD). OBJECTIVES: The aim was to confirm the pathogenesis of KCNJ10 variants and the relationship between KCNJ10 variants and PKD phenotypes. METHODS: The whole-exome sequencing followed by Sanger sequencing were used to screen the potential pathogenic KCNJ10 variants in a cohort of PKD patients. Functional studies were performed to check the pathogenicity of the variants. The clinical characteristics of KCNJ10-related PKD patients reported to date were reviewed. RESULTS: Five heterozygous KCNJ10 variants including c.76C>T (p.R26*), c.436C>T (p.L146F), c.484A>G (p.T162A), c.524G>A (p.R175Q), and c.923del (p.G308Afs*17), were detected in five pedigrees and three sporadic patients. All variants had extremely low frequency in normal populations and were highly conserved between species. They influenced the location or expression of potassium inwardly rectifying channel (Kir) 4.1 and resulted in the Kir currents of cell decreased to varied degrees. Up to date, 31 KCNJ10 variants had been reported to manifest as PKD, and a significant majority (22/31, 71%) were in the cytoplasmic domain near the C-terminus. Notably, the KCNJ10-related PKD patients showed a pronounced male predominance. CONCLUSIONS: The study confirmed the correlation between PKD and the loss-of-function of Kir4.1 resulted from heterozygous KCNJ10 variants. The distribution bias of PKD-related KCNJ10 variants as well as the male predominance in affected individuals shed light on the mechanism investigation of this subtype of PKD. © 2026 International Parkinson and Movement Disorder Society.

Related

• Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3—a subgroup of K+ channelopathies
• Novel Kinesin Family Member 1A Variants Linked to Atypical Parkinsonism Elicit Altered Neuronal Transactive Response DNA Binding Protein 43 kDa Interactions and Dendritic Atrophy
• Large-scale functional assessment of variants of the potassium channel Kir2.1: Clinical and comparative insights
• PRKN-linked familial Parkinson’s disease: cellular and molecular mechanisms of disease-linked variants
• Co-occurrence of Loss-of-Function GCK and ABCC8 Variants in a Pedigree With a Spectrum of Dysglycemia