GPD1L Mutations and SCN5A Phosphorylation in Brugada Syndrome

Abstract

The gene GPD1L encodes the glycerol phosphate dehydrogenase 1-like protein with homology to glycerol phosphate dehydrogenase (GPD1). Prior to the discovery of mutations in GPD1L in patients with Brugada Syndrome and Sudden Infant Death Syndrome (SIDS), the importance and function of this enzyme was unknown. GPD1 catalyzes the reversible conversion of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate (DHAP). We hypothesized that like its namesake GPD1, GPD1L catalyzed the reaction of G3P to DHAP. A loss-of-function of GPD1L’s enzymatic activity would be expected to increase levels of G3P, which ultimately serves as a substrate for PKC-mediated phosphorylation of SCN5A, a known down-regulator of cardiac sodium channel (SCN5A) function. We found that mutations in GPD1L caused a loss of enzymatic function, increased phosphorylation of SCN5A, and decreased peak sodium current consistent with the molecular phenotype of Brugada Syndrome. The G3P to DHAP conversion also causes reduction of NAD+ to NADH, and loss of GPD1L function may also increase reactive oxygen species producing additional effects on SCN5A and other ion channels. The “natural experiment” of GPD1L mutations found in patients has given insight into basic regulatory mechanisms of cardiac excitability.