Selectivity Filter KCND3 Variant Causes Spinocerebellar Ataxia 19/22 and KV4.3 Functional Loss.
Selectivity Filter KCND3 Variant Causes Spinocerebellar Ataxia 19/22 and KV4.3 Functional Loss.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Changhua, TW · Author affiliation
Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan.Location evidence
Taipei, TW · Author affiliation
Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.Location evidence
Taichung, TW · Author affiliation
Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.Location evidence
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Original abstract
BACKGROUND: Spinocerebellar ataxia type 19/22 (SCA19/22) is a rare autosomal dominant neurodegenerative disorder caused by KCND3 variants encoding the KV4.3 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 KV4.3 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 KV4.3 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.