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

Area of Science:

• Neurogenetics
• Channelopathies
• Movement Disorders

Background:

• Over 60% of paroxysmal kinesigenic dyskinesia (PKD) cases have uncertain genetic causes.
• Identifying novel genetic contributors is crucial for understanding PKD pathogenesis.

Purpose of the Study:

• To elucidate the novel genetic contribution to paroxysmal kinesigenic dyskinesia (PKD).
• To investigate the functional impact of identified genetic variants on neuronal excitability.

Main Methods:

• Whole-exome sequencing of 476 probands with uncertain PKD genetic causes.
• Case-control analysis to identify candidate genes, followed by whole-cell patch-clamp recordings.
• Development of a Kcnj10 heterozygous knockout mouse model for in vivo functional studies.

Main Results:

• Heterozygous KCNJ10 variants were detected in 3.07% of PKD probands, often associated with milder phenotypes than PRRT2 variants.
• KCNJ10 variants altered Kir4.1 channel function, reduced cell currents, and led to elevated neural excitability in knockout mice.
• Kcnj10 knockout mice exhibited dystonic posture, impaired motor coordination, and motor learning deficits.

Conclusions:

• Heterozygous KCNJ10 variants are implicated in paroxysmal kinesigenic dyskinesia (PKD).
• Impaired Kir4.1 channel function contributes to abnormal neuronal excitability and PKD pathogenesis.