Journal article
Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) mutations in sudden infant death syndrome
Circulation (New York, N.Y.), Vol.116(20), pp.2253-2259
2007
DOI: 10.1161/CIRCULATIONAHA.107.704627
PMCID: PMC3332545
PMID: 17967976
Abstract
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 approximately 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.
Details
- Title: Subtitle
- Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1-like gene (GPD1-L) mutations in sudden infant death syndrome
- Creators
- David W VAN NORSTRAND - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn, United StatesCarmen R VALDIVIA - Departments of Medicine and Physiology University of Wisconsin, Madison, United StatesDavid J TESTER - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn, United StatesKazuo UEDA - Departments of Medicine and Physiology University of Wisconsin, Madison, United StatesBarry LONDON - Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pa, United StatesJonathan C MAKIELSKI - Departments of Medicine and Physiology University of Wisconsin, Madison, United StatesMichael J ACKERMAN - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn, United States
- Resource Type
- Journal article
- Publication Details
- Circulation (New York, N.Y.), Vol.116(20), pp.2253-2259
- DOI
- 10.1161/CIRCULATIONAHA.107.704627
- PMID
- 17967976
- PMCID
- PMC3332545
- NLM abbreviation
- Circulation
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Publisher
- Lippincott Williams & Wilkins; Hagerstown, MD
- Language
- English
- Date published
- 2007
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984025669102771
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