Coexpression of the A280V GPD1-L mutation with SCN5A reduced inward Na+ currents by approximately 50% (P<0.005) and decreased SCN5A cell surface expression by 31% (P=0.01).
The A280V mutation in the GPD1-L gene decreases SCN5A surface membrane expression and inward Na+ current, identifying it as a novel genetic cause of Brugada syndrome.
Effect estimate: approximately 50% reduction
p-value: p=<0.005
BACKGROUND: Brugada syndrome is a rare, autosomal-dominant, male-predominant form of idiopathic ventricular fibrillation characterized by a right bundle-branch block and ST elevation in the right precordial leads of the surface ECG. Mutations in the cardiac Na+ channel SCN5A on chromosome 3p21 cause approximately 20% of the cases of Brugada syndrome; most mutations decrease inward Na+ current, some by preventing trafficking of the channels to the surface membrane. We previously used positional cloning to identify a new locus on chromosome 3p24 in a large family with Brugada syndrome and excluded SCN5A as a candidate gene. METHODS AND RESULTS: We used direct sequencing to identify a mutation (A280V) in a conserved amino acid of the glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene. The mutation was present in all affected individuals and absent in >500 control subjects. GPD1-L RNA and protein are abundant in the heart. Compared with wild-type GPD1-L, coexpression of A280V GPD1-L with SCN5A in HEK cells reduced inward Na+ currents by approximately 50% (P<0.005). Wild-type GPD1-L localized near the cell surface to a greater extent than A280V GPD1-L. Coexpression of A280V GPD1-L with SCN5A reduced SCN5A cell surface expression by 31+/-5% (P=0.01). CONCLUSIONS: GPD1-L is a novel gene that may affect trafficking of the cardiac Na+ channel to the cell surface. A GPD1-L mutation decreases SCN5A surface membrane expression, reduces inward Na+ current, and causes Brugada syndrome.
London et al. (Mon,) conducted a other in Brugada syndrome. A280V mutation in GPD1-L gene vs. Wild-type GPD1-L was evaluated on Inward Na+ currents (approximately 50% reduction, p=<0.005). Coexpression of the A280V GPD1-L mutation with SCN5A reduced inward Na+ currents by approximately 50% (P<0.005) and decreased SCN5A cell surface expression by 31% (P=0.01).