Document Detail


Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome.
MedLine Citation:
PMID:  17967976     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-10-29
Journal Detail:
Title:  Circulation     Volume:  116     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2007 Nov 
Date Detail:
Created Date:  2007-11-13     Completed Date:  2007-12-18     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2253-9     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
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
Grant Support
ID/Acronym/Agency:
HD42569/HD/NICHD NIH HHS; R01 HD042569/HD/NICHD NIH HHS; R01 HD042569-06/HD/NICHD NIH HHS; R01 HD042569-07/HD/NICHD NIH HHS; R01HD042569/HD/NICHD NIH HHS; R01HL71092/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
EC 1.1.-/GPD1-L protein, human; EC 1.1.-/Glycerolphosphate Dehydrogenase; EC 1.1.-/Sugar Alcohol Dehydrogenases
Comments/Corrections

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