An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation

Area of Science:

• Cardiology
• Genetics
• Molecular Biology

Background:

• Calcium regulation is vital for heart function.
• Variants in the Ca_v1.2 calcium channel are linked to cardiac arrhythmias.
• Brugada syndrome, short QT syndrome, early repolarisation syndrome, and idiopathic ventricular fibrillation are serious heart rhythm disorders.

Purpose of the Study:

• To determine the frequency and pathogenicity of Ca_v1.2 variants in patients with specific arrhythmic syndromes.
• To investigate the functional impact of identified Ca_v1.2 variants on channel activity.

Main Methods:

• Screening of CACNA1C, CACNB2, and CACNA2D1 genes in 65 probands with arrhythmic syndromes.
• Site-directed mutagenesis to introduce missense variants into the Ca_v1.2 alpha subunit.
• Patch-clamp electrophysiology to assess channel function and pathogenicity of variants.

Main Results:

• Six missense variants in CACNA1C were identified in five individuals.
• Five variants showed no significant impact on channel function.
• The Ca_vα_1c-T1787M variant, found in two patients with cardiac arrest and idiopathic ventricular fibrillation, reduced calcium and barium currents.
• Ca_vα_1c-T1787M increases auto-inhibition and voltage-dependent inhibition of the channel.

Conclusions:

• The Ca_vα_1c-T1787M variant is a loss-of-function variant associated with ventricular arrhythmias.
• This variant, prevalent in the African population (0.8%), represents a novel risk factor for cardiac arrhythmias.
• Understanding Ca_v1.2 variants is crucial for diagnosing and managing inherited arrhythmia syndromes.