Abstract
Abstract 2968: Postmortem Genetic Testing of the GPD1-L-Encoded Glycerol-3-Phosphate Dehydrogenase 1-Like Protein in Sudden Infant Death Syndrome
Circulation (New York, N.Y.), Vol.116(suppl_16)
10/16/2007
DOI: 10.1161/circ.116.suppl_16.II_663-a
Abstract
Introduction: Approximately 10 – 15% of sudden infant death syndrome (SIDS) may be caused by cardiac channelopathies including Brugada syndrome (BrS). Type 1 BrS (BrS1), due to mutations in the SCN5A-encoded sodium channel, accounts for approximately 20% of BrS. Recently, a novel mutation in glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) disrupted trafficking of SCN5A in a multi-generational family with BrS. We hypothesized that mutations in GPD1-L may be responsible for some cases of SIDS.
Methods: Using DHPLC 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 228 anonymous cases of SIDS (86 females, 142 males, average age = 3 + 2 months, range 6 hours to 12 months).
Results: Three putative, SIDS-associated GPD1-L missense mutations, E83K, I124V, and R273C, were discovered in a three-month-old white male, a five-week-old white female, and a one-month-old white male, respectively. All mutations occurred in highly conserved residues and were absent in 600 reference alleles. Compared to wild type GPD1-L, GPD1-L mutations co-expressed with SCN5A in heterologous HEK cells produced a 60% reduction in peak sodium current density (p<0.004). Adenovirus-mediated gene transfer of the E83K-GPD1-L mutation into neonatal mouse myocytes markedly attenuated the sodium current as well (p<0.01). These decreases in current density are consistent with sodium channel loss-of-function diseases like BrS.
Conclusion: This study is the first to report mutations in GPD1-L as a pathogenic cause for a small subset (~1%) of SIDS 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 pro-arrhythmic substrate.
Details
- Title: Subtitle
- Abstract 2968: Postmortem Genetic Testing of the GPD1-L-Encoded Glycerol-3-Phosphate Dehydrogenase 1-Like Protein in Sudden Infant Death Syndrome
- Creators
- David W Van Norstrand - Mayo Clinic College of Medicine, Rochester, MNCarmen R Valdivia - University of Wisconsin–MadisonDavid J Tester - Mayo Clinic College of Medicine, Rochester, MNKazuo Ueda - University of Wisconsin–MadisonBarry London - University of PittsburghJonathan C Makielski - University of Wisconsin–MadisonMichael J Ackerman - Mayo Clinic College of Medicine, Rochester, MN
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.116(suppl_16)
- DOI
- 10.1161/circ.116.suppl_16.II_663-a
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 10/16/2007
- Academic Unit
- Cardiovascular Medicine; Internal Medicine; Molecular Physiology and Biophysics
- Record Identifier
- 9984303005402771
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