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http://purl.uniprot.org/citations/17967976http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/17967976http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/17967976http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.107.704627"xsd:string
http://purl.uniprot.org/citations/17967976http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.107.704627"xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Ueda K."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Ueda K."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Ackerman M.J."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Ackerman M.J."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Tester D.J."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Tester D.J."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Valdivia C.R."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Valdivia C.R."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Makielski J.C."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Makielski J.C."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"London B."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"London B."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Van Norstrand D.W."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/author"Van Norstrand D.W."xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/date"2007"xsd:gYear
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/date"2007"xsd:gYear
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/name"Circulation"xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/name"Circulation"xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/pages"2253-2259"xsd:string
http://purl.uniprot.org/citations/17967976http://purl.uniprot.org/core/pages"2253-2259"xsd:string
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