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(Circulation. 2007;116:2260-2268.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

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; 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.).

Correspondence to Barry London, MD, PhD, Cardiovascular Institute, University of Pittsburgh Medical Center, Scaife S-572, 200 Lothrop St, Pittsburgh, PA 15213–2582. E-mail londonb{at}upmc.edu

Received March 24, 2007; accepted August 31, 2007.

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.

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