Selectivity Filter KCND3 Variant Causes Spinocerebellar Ataxia 19/22 and K V 4 .3 Functional Loss

Abstract Background Spinocerebellar ataxia type 19/22 (SCA19/22) is a rare autosomal dominant neurodegenerative disorder caused by KCND3 variants encoding the K V 4.3 potassium channel. While most pathogenic variants result in loss‐of‐function (LOF), no pathogenic variants were previously identified in the channel's selectivity filter, a critical domain for ion selectivity. Objectives To elucidate the genetic cause and functional LOF mechanisms underlying severe early‐onset cerebellar ataxia and neurodevelopmental impairment in monozygotic twins. Methods We evaluated twins presenting with early‐onset cerebellar ataxia, developmental delay, and cognitive impairment. Whole‐exome sequencing (WES) identified a KCND3 c.1103T>C (p.L368P) variant. Functional impacts were assessed through HEK293T cell protein expression, Xenopus oocyte electrophysiology, and structural homology modeling. Results WES identified a heterozygous de novo p.L368P variant in the “TLGYG” selectivity filter sequence. Modeling predicted a pore radius reduction, blocking potassium permeation. Biochemical analyses revealed markedly reduced protein expression and impaired trafficking. Electrophysiological recordings confirmed complete potassium current loss and a strong dominant‐negative effect on wild‐type K V 4.3 currents. Clinically, the twins exhibited severe intellectual disability, developmental delay, and cerebellar atrophy with pontine flattening, without epilepsy. Conclusions Identifying the first pathogenic variant in the K V 4.3 selectivity filter highlights its critical role in channel proteostasis and ion conductance. The p.L368P variant produces a pronounced LOF phenotype and broadens the SCA19/22 clinical spectrum, indicating the filter's structural integrity is a key determinant of disease severity. © 2026 International Parkinson and Movement Disorder Society.