Published Online
on October 29, 2007

A more recent version of this article appeared on November 13, 2007

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Submitted on March 24, 2007
Accepted on August 31, 2007

Mutation in Glycerol-3-Phosphate Dehydrogenase 1–Like Gene (GPD1-L) Decreases Cardiac Na⁺ Current and Causes Inherited Arrhythmias

Barry London MD, PhD^*, Michael Michalec MS, Haider Mehdi PhD, Xiaodong Zhu PhD, Laurie Kerchner BS, Shamarendra Sanyal PhD, Prakash C. Viswanathan PhD, Arnold E. Pfahnl MD, PhD, Lijuan L. Shang PhD, Mohan Madhusudanan MD, Catherine J. Baty PhD, Stephen Lagana BA, Ryan Aleong MD, Rebecca Gutmann RN, BSN, Michael J. Ackerman MD, PhD, Dennis M. McNamara MD, Raul Weiss MD, and Samuel C. Dudley Jr MD, PhD

From the Cardiovascular Institute (B.L., M. Michalec, H.M., X.Z., L.K., P.C.V., M. Madhusadanan, S.L., R.A., R.G., D.M.M.) and Department of Cell Biology and Physiology (B.L., P.C.V., C.J.B.), University of Pittsburgh, Pittsburgh Pa; Department of Cardiology, Emory University and Atlanta VA Medical Center, Atlanta, Ga (S.S., A.E.P., L.L.S., S.C.D.); Division of Cardiology, Mayo Clinic College of Medicine, Rochester, Minn (M.J.A.); and Division of Cardiology, Ohio State University, Columbus (R.W.).

^* To whom correspondence should be addressed. E-mail: londonb{at}upmc.edu.

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.

Key words: arrhythmia • electrophysiology • genetics • ion channels • sodium

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