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Mutation in glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias
Journal article   Open access   Peer reviewed

Mutation in glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) decreases cardiac Na+ current and causes inherited arrhythmias

Barry LONDON, Michael MICHALEC, Catherine J BATY, Stephen LAGANA, Ryan ALEONG, Rebecca GUTMANN, Michael J ACKERMAN, Dennis M MCNAMARA, Raul WEISS, Samuel C DUDLEY, …
Circulation (New York, N.Y.), Vol.116(20), pp.2260-2268
2007
DOI: 10.1161/CIRCULATIONAHA.107.703330
PMCID: PMC3150966
PMID: 17967977
url
https://doi.org/10.1161/CIRCULATIONAHA.107.703330View
Published (Version of record) Open Access

Abstract

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 ≈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 ≈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.
 Cardiovascular System Heart Cardiology. Vascular system Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Pharmacology. Drug treatments Biological and medical sciences Medical sciences Heart failure, cardiogenic pulmonary edema, cardiac enlargement Blood and lymphatic vessels Antihypertensive agents

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