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

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.