Differential negative dominance by KCNA2 variants associated with global developmental delay suggests KCNA2 haploinsufficiency in humans - PubMed
6 hours ago
- #KCNA2
- #ion channels
- #haploinsufficiency
- KCNA2 encodes KV1.2 potassium channel subunits crucial for neuronal excitability, with variants linked to developmental epileptic encephalopathy (DEE) type 32.
- Two KCNA2 variants, p.H310D and p.G318D (aspartate substitutions at conserved positions), cause loss of function by abolishing channel currents and surface trafficking in frog oocytes and primate cells.
- p.H310D is strongly negative-dominant, reducing conductance to 7% in heterozygous cells and halving wild-type subunit trafficking, while p.G318D is weakly negative-dominant, with 32% conductance and 86% wild-type trafficking.
- The findings, based on differential negative dominance and patient symptoms, suggest KCNA2 is haploinsufficient in humans, indicating that reduced gene dosage contributes to global developmental delay.