Characterization of Three Distinct Loss-of-Function Cav2.3 Variants.

Area of Science:

• Neuroscience
• Genetics
• Biophysics

Background:

• De novo variants in the CACNA1E gene, encoding the Cav2.3 channel, are associated with severe neurodevelopmental disorders like developmental and epileptic encephalopathy.
• Previously identified CACNA1E variants have demonstrated gain-of-function effects on channel biophysical properties.

Purpose of the Study:

• To functionally characterize three pathogenic CACNA1E variants (H151L, M163T, R1182C).
• To investigate the biophysical mechanisms underlying these variants' effects on Cav2.3 channel function.
• To expand the known clinical spectrum of CACNA1E channelopathies.

Main Methods:

• Electrophysiology to measure channel function.
• Structural modeling to understand variant effects at a molecular level.

Main Results:

• M163T and R1182C variants caused depolarizing shifts in activation voltage-dependence.
• R1182C variant also exhibited reduced peak current density.
• H151L variant selectively slowed recovery from inactivation.

Conclusions:

• These findings provide the first mechanistic evidence for loss-of-function Cav2.3 pathogenic variants.
• This expands the clinical spectrum of CACNA1E channelopathies beyond gain-of-function effects.
• Understanding these loss-of-function mechanisms is crucial for diagnosing and potentially treating related neurological disorders.