Differential negative dominance by KCNA2 variants associated with global developmental delay suggests KCNA2 haploinsufficiency in humans.
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Boon PX, Jauregi-Miguel A, Yasarbas SS, Pozzi S, Karlsson U, Husami A, Ko C, Shillington A, Pantazis A
J Physiol 604 (8) 3413-3430 [2026-04-00; online 2026-03-31]
KCNA2 encodes the pore-forming subunits of the voltage-gated, potassium-selective channel KV1.2, which controls the excitability of both central and peripheral neurons. Either gain- or loss-of-function KCNA2 variants can cause severe neurological disease, assigned developmental epileptic encephalopathy (DEE) type 32. Here, we report and characterize two apparently similar variants, p.H310D and p.G318D, both discovered in patients with global developmental delay and involving aspartate substitutions at positions highly conserved in the KV-channel superfamily. We found that both are loss-of-function variants, completely abolishing channel current and subunit trafficking. Channel constructs of KV1.2-variant subunits in tandem with KV1.4 had a conductance with inhibited voltage-dependence, with shifted half-activation potentials by 27 and 19 mV for p.H310D and p.G318D, respectively. p.H310D was strongly negative-dominant: heterozygous cells exhibited only 7% conductance relative to homozygous wild-type, while only half of wild-type subunits could traffic to the surface. In contrast, p.G318D exhibited weaker negative dominance, with 32% conductance in heterozygous cells and 86% wild-type-subunit trafficking. Taken together with the p.G318D-patient's neurological symptoms, the latter suggests that KCNA2 is a haploinsufficient gene in humans. KEY POINTS: KCNA2 encodes the pore-forming subunits of the KV1.2 voltage-activated, K+-selective ion channel, which regulates electrical signalling in neurons. We characterized two KCNA2 variants from patients with global developmental delay. Both variants are aspartate substitutions of proximal, highly conserved positions in KV-channels: p.H310D and p.G318D. In frog oocytes and in primate cells, both variants cause loss of KCNA2 function, abolishing currents and surface trafficking, and inhibiting channel voltage-dependent opening. p.H310D is strongly negative-dominant, potently suppressing wild-type subunit functional expression. In contrast, p.G318D is weakly negative-dominant, leaving wild-type subunits largely unaffected. This suggests that KCNA2 is a haploinsufficient gene in humans.
Clinical Genomics Linköping [Service]
PubMed 41914769
DOI 10.1113/JP290728
Crossref 10.1113/JP290728