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 22, 2007
Accepted on August 31, 2007

Molecular and Functional Characterization of Novel Glycerol-3-Phosphate Dehydrogenase 1–Like Gene (GPD1-L) Mutations in Sudden Infant Death Syndrome

David W. Van Norstrand BS, Carmen R. Valdivia MD, David J. Tester BS, Kazuo Ueda MD, PhD, Barry London MD, PhD, Jonathan C. Makielski MD, and Michael J. Ackerman MD, PhD^*

From the Department of Molecular Pharmacology and Experimental Therapeutics (D.W.V., D.J.T., M.J.A.), the Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), and the Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology (M.J.A.), Mayo Clinic, Rochester, Minn; the Departments of Medicine and Physiology (C.R.V., K.U., J.C.M.), University of Wisconsin, Madison; and the Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa (B.L.).

^* To whom correspondence should be addressed. E-mail: ackerman.michael{at}mayo.edu.

Background—Autopsy-negative sudden unexplained death, including sudden infant death syndrome, can be caused by cardiac channelopathies such as Brugada syndrome (BrS). Type 1 BrS, caused by mutations in the SCN5A-encoded sodium channel, accounts for 20% of BrS. Recently, a novel mutation in the glycerol-3-phosphate dehydrogenase 1–like gene (GPD1-L) disrupted trafficking of SCN5A in a multigenerational family with BrS. We hypothesized that mutations in GPD1-L may be responsible for some cases of sudden unexplained death/sudden infant death syndrome.

Methods and Results—Using denaturing high-performance liquid chromatography and direct DNA sequencing, we performed comprehensive open-reading frame/splice site mutational analysis of GPD1-L on genomic DNA extracted from necropsy tissue of 83 unrelated cases of sudden unexplained death (26 females, 57 males; average age, 14.6±10.7 years; range, 1 month to 48 years). A putative, sudden unexplained death–associated GPD1-L missense mutation, E83K, was discovered in a 3-month-old white boy. Further mutational analysis was then performed on genomic DNA derived from a population-based cohort of 221 anonymous cases of sudden infant death syndrome (84 females, 137 males; average age, 3±2 months; range, 3 days to 12 months), revealing 2 additional mutations, I124V and R273C, in a 5-week-old white girl and a 1-month-old white boy, respectively. All mutations occurred in highly conserved residues and were absent in 600 reference alleles. Compared with wild-type GPD1-L, GPD1-L mutations coexpressed with SCN5A in heterologous HEK cells produced a significantly reduced sodium current (P<0.01). Adenovirus-mediated gene transfer of the E83K–GPD1-L mutation into neonatal mouse myocytes markedly attenuated the sodium current (P<0.01). These decreases in current density are consistent with sodium channel loss-of-function diseases like BrS.

Conclusions—The present study is the first to report mutations in GPD1-L as a pathogenic cause for a small subset of sudden infant death syndrome via a secondary loss-of-function mechanism whereby perturbations in GPD1-L precipitate a marked decrease in the peak sodium current and a potentially lethal BrS-like proarrhythmic substrate.

Key words: arrhythmia • death, sudden • genetics • ion channels • pediatrics

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