KCNC1 – Progressive Myoclonus Epilepsy

KCNC1 encodes the voltage‐gated potassium channel subunit Kv3.1, predominantly expressed in fast‐spiking GABAergic interneurons and cerebellar neurons. Heterozygous de novo variants in KCNC1 underlie Progressive Myoclonus Epilepsy with onset in childhood, characterized by action myoclonus, generalized tonic–clonic seizures, and ataxia.

The recurrent de novo variant c.959G>A (p.Arg320His) was identified in 11/84 unrelated PME cases and two additional affected individuals in a secondary cohort (PMID:25401298). A separate next‐generation sequencing study detected KCNC1 variants in 3/13 unrelated PME patients (PMID:34786481). All variants occurred de novo in unrelated probands, supporting an autosomal dominant inheritance model with no reported familial segregation.

To date, the variant spectrum in PME is led by c.959G>A (p.Arg320His), with additional rare missense changes such as those affecting channel gating or phosphorylation sites. The predominant mechanism is dominant‐negative loss of function, although gain‐of‐function effects on channel regulation have been described in other KCNC1‐related encephalopathies.

Functional assays demonstrate that p.Arg320His exerts a dominant‐negative effect on whole‐cell Kv3.1 currents in Xenopus oocytes and mammalian expression systems, markedly slowing activation and reducing current density (PMID:25401298). The de novo p.Ala513Val variant fails to be phosphorylated by PKC, further implicating channel modulation in disease pathogenesis (PMID:34232791).

A novel transgenic mouse model expressing KCNC1‐p.Ala421Val recapitulates treatment‐resistant seizures, interneuronal hypoexcitability, and premature lethality, confirming the central role of Kv3.1 dysfunction in PME (PMID:39386579).

Collectively, 13 unrelated probands with the recurrent Arg320His variant and functional concordance across multiple models establish a Definitive gene‐disease association. Key take‐home: KCNC1 de novo variants should be considered in unexplained childhood PME, and functional data support targeted diagnostics and therapeutic repurposing.

References

• Nature genetics • 2015 • A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. PMID:25401298
• Neurology. Genetics • 2021 • Progressive Myoclonus Epilepsies: Diagnostic Yield With Next-Generation Sequencing in Previously Unsolved Cases. PMID:34786481
• Journal of neurophysiology • 2021 • A KCNC1 mutation in epilepsy of infancy with focal migrating seizures produces functional channels that fail to be regulated by PKC phosphorylation. PMID:34232791
• Epilepsia • 2021 • Progressive myoclonus epilepsy KCNC1 variant causes a developmental dendritopathy. PMID:33735526
• bioRxiv • 2024 • Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy. PMID:39386579

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