Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome.

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.

• Authors: David W Van Norstrand, Carmen R Valdivia, David J Tester, Kazuo Ueda, Barry London, Jonathan C Makielski, Michael J Ackerman
• Journal: Circulation (Circulation) Vol. 116 Issue 20 Pg. 2253-9 (Nov 13 2007) ISSN: 1524-4539 [Electronic] United States
• PMID: 17967976 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• GPD1L protein, human
• Glycerolphosphate Dehydrogenase
• Sugar Alcohol Dehydrogenases

Topics

• Adolescent
• Adult
• Cell Line
• Child
• Child, Preschool
• Cohort Studies
• DNA Mutational Analysis
• Death, Sudden (epidemiology, etiology)
• Female
• Genetic Predisposition to Disease (epidemiology)
• Glycerolphosphate Dehydrogenase (genetics, metabolism)
• Humans
• Infant
• Infant, Newborn
• Kidney (cytology)
• Male
• Middle Aged
• Mutation
• Sudden Infant Death (epidemiology, genetics)
• Sugar Alcohol Dehydrogenases (genetics, metabolism)