KCND3 – Spinocerebellar ataxia type 19/22

KCND3 encodes the voltage-gated potassium channel subunit Kv4.3, which mediates the transient outward K+ current (Ito) critical for cerebellar Purkinje cell excitability. Spinocerebellar ataxia type 19 (SCA19) and type 22 (SCA22) are allelic autosomal dominant neurodegenerative disorders characterized by progressive cerebellar ataxia, cognitive impairment, dysarthria, and variable additional features including myoclonus and seizures. KCND3 variants underlie the disease through dominant-negative and loss-of-function mechanisms.

Genetic evidence includes multiple unrelated pedigrees and sporadic cases. A Swedish family spanning five generations harbors the missense variant c.1130C>T (p.Thr377Met) PMID:29527639. The recurrent p.Val374Ala mutation has been reported in two independent families (Italian and U.S.) PMID:35949253. A series of six Latin American patients carrying c.1150G>A (p.Gly384Ser) further expands the spectrum PMID:38180701. Additional heterozygous variants, including in‐frame deletions and missense changes clustering in transmembrane and pore regions, have been identified in at least five kindreds worldwide PMID:23280837.

Segregation analysis demonstrates co-segregation of KCND3 variants with disease in multiple families, including at least 5 affected relatives carrying p.Thr377Met in the Swedish pedigree PMID:29527639. Combined, there are 8 probands (1 Swedish [PMID:29527639], 1 Italian [PMID:35949253], 6 Latin American [PMID:38180701]) and robust multi-family segregation.

The variant spectrum is dominated by missense substitutions (e.g., p.Thr377Met, p.Val374Ala, p.Gly384Ser), an in-frame deletion (p.Phe227del), and rare duplications affecting the voltage-sensor domain. Founder or recurrent alleles have been observed in European and Latin American populations. Phenotypic variability spans early-onset rapid progression to late-onset slowly progressive ataxia, with additional features such as dystonia, myoclonus, and seizures in some carriers.

Functional studies in heterologous systems show that SCA19/22-associated KCND3 mutants produce loss-of-function effects with reduced peak Ito, altered inactivation kinetics, and dominant-negative suppression of wild-type channel trafficking and gating PMID:31293010. Co-expression with the KChIP2 auxiliary subunit partially rescues current for some variants, confirming a dominant-negative mechanism.

An in vivo Drosophila model demonstrates that disease-causing KCND3 mutants disrupt endogenous Shal proteostasis, leading to locomotor defects and neurodegeneration, which are ameliorated by overexpression of molecular chaperones HSC70 and HSP83 PMID:40293501. These findings corroborate the pathogenic role of proteostasis impairment in SCA19/22.

Overall, the association between KCND3 and SCA19/22 is definitive based on replication in >5 families, >8 probands, multi-generation segregation, and concordant in vitro and in vivo functional data. KCND3 genetic testing is clinically useful for diagnosis and family counseling, and functional assays provide a platform for future therapeutic screening.

References

• Cerebellum (London, England) • 2018 • Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19. PMID:29527639
• Neurology. Genetics • 2022 • A Second Case With the V374A KCND3 Pathogenic Variant in an Italian Patient With Early-Onset Spinocerebellar Ataxia. PMID:35949253
• Cerebellum (London, England) • 2024 • The Phenotypic Spectrum of Spinocerebellar Ataxia Type 19 in a Series of Latin American Patients. PMID:38180701
• Annals of neurology • 2012 • Mutations in KCND3 cause spinocerebellar ataxia type 22. PMID:23280837
• Human mutation • 2019 • Novel SCA19/22-associated KCND3 mutations disrupt human KV 4.3 protein biosynthesis and channel gating. PMID:31293010
• Cellular and molecular life sciences : CMLS • 2025 • Restoration of Shal/KV4 proteostasis and motor function in a Drosophila model of spinocerebellar ataxia type 19/22. PMID:40293501

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