Kv3.1 (voltage-gated potassium channel) encoded by KCNC1 (NM_001112741.2) is evolutionarily highly conserved. They are predominantly expressed in fast-spiking neurons (i.e. GABAergic interneurons, Purkinje cells and auditory neurons) which facilitate high-frequency firing. Pathogenic variants in KCNC1 may lead to impaired firing of e.g. GABAergic interneurons and lead to neuronal disinhibition.
Type of gene variants, and suspected pathophysiologic mechanism:
Different missense-, nonsense- and frameshift-variants have been identified in patients with a KCNC1-related disorder – also see clinical characteristics. Both loss-of-function (LoF) and dominant-negative loss-of-function have been described as possible pathomechanisms for KCNC1-disorders.
Muona et al. first described the recurrent c.959G>A, p.Arg320His variant in MEAK patients, which affects a positively charged arginine in the voltage-sensing S4 domain. Functional analysis revealed a LoF with a dominant-negative reduction of current amplitude measured in Xenopus Oocytes.
Subsequently, Poirier et al. identified a truncating variant (c.1015C>T, p.Arg399Ter) in a family with intellectual disability without seizures. KCNC1 transcript was significantly reduced (>50%) in patient’s fibroblasts indicating haploinsufficiency as pathomechanism. However, a dominant-negative effect was measured when Arg339Ter mutant channel was co-expressed with wildtype channel, indicating that the mutant protein may escape NMD and cause additional damaging effect (Cameron et al. 2019).
Other truncating KCNC1 variants (c.1474C>T, p.Gln492Ter) as well as missense variants (c.1196C>T, p.Thr399Met; c.950G>A, p.Arg317His) have been identified in patients with intellectual disability without seizures. The two missense variants (p.Thr399Met, p.Arg317His) as well as another c.949C>A, p.Arg317Ser (identified in a patient with epilepsy and developmental delay) showed similar dominant-negative LoF effect as the p.Arg320His variant.
The recurrent c.1262C>T, p.Ala421Val variant, which causes developmental and epileptic encephalopathy with ataxia showed a LoF. No dominant-negative function was measured by Cameron et al., while Park et al. have observed a mild dominant-negative effect for this variant.
The c.623G>A, p.Cys208Tyr variant, identified in a patient with non-progressive mild myoclonus, showed a LoF without any dominant-negative effect.
The c.1538C>T, p.Ala513Val variant, identified in a patient with epilepsy of infancy and focal migrating seizures, has shown to disrupt channel regulation by phosphorylation at Ser503 residue.
In summary, functional analysis of pathogenic KCNC1 variants showed either a LoF, dominant-negative LoF or disruption of regulatory functions. However, the individual studies have not yet been able to provide a clear explanation for the clinical differences that occur in KCNC1 patients.
Diagnostic testing:
Diagnosis can be made by comprehensive genomic testing (single-gene testing, gene panel, exome sequencing, genome sequencing). KCNC1 variants should be considered in patients with one or more of the following symptoms: myoclonus (mild and severe), ataxia, generalized seizures, myoclonic seizures, absence seizures and developmental delay/intellectual disability.
KCNC1