KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Global developmental delay (GDD) is a heterogeneous neurodevelopmental disorder.
• Voltage-gated potassium channels (Kv) play crucial roles in neuronal function.
• Kv4.2 channels, encoded by KCND2, are implicated in neuronal excitability.

Purpose of the Study:

• To investigate the pathogenicity of KCND2 variants identified in individuals with early-onset GDD.
• To elucidate the functional impact of Kv4.2 channel mutations on channel gating.
• To explore the role of auxiliary subunits in modulating mutant Kv4.2 channel function.

Main Methods:

• Heterologous expression of wild-type and mutant Kv4.2 channels in Xenopus oocytes.
• Two-electrode voltage-clamp recordings to assess channel gating kinetics (activation and inactivation).
• Co-expression with auxiliary subunits (KChIP2, DPP6) to study heteromeric and heteromeric ternary channel complexes.

Main Results:

• All identified KCND2 variants (E323K, P403A, V404L, V404M) exhibited altered channel gating, primarily slowed and incomplete inactivation.
• The P403A variant also showed slowed activation.
• Auxiliary subunits modulated mutant channel function, with significant gating impairment observed in heteromeric ternary complexes for P403A, V404L, and V404M variants.

Conclusions:

• KCND2 variants causing Kv4.2 channel gating impairment are etiological factors in early-onset monogenic GDD.
• Loss-of-function or gain-of-function mechanisms associated with these variants contribute to neurodevelopmental deficits.
• Gain-of-function mechanisms of V404 substitutions may increase susceptibility to epileptic seizures.