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

Article

关键词: LONG-QT SYNDROME;    SICK SINUS SYNDROME;    LATE SODIUM CURRENT;    CARDIAC DEATH;    BRUGADA-SYNDROME;    UNEXPECTED DEATHS;    UNEXPLAINED DEATH;    SCN5A;    ARRHYTHMIA;    MECHANISM;   

DOI  :  10.1161/CIRCULATIONAHA.107.704627

来源: SCIE

【 摘 要 】

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 approximate to 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.

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