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


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.
Van Norstrand
David W
DW
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.
Valdivia
Carmen R
CR
Tester
David J
DJ
Ueda
Kazuo
K
London
Barry
B
Makielski
Jonathan C
JC
Ackerman
Michael J
MJ
D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003645:Death, Sudden / Q000453:epidemiology / Q000209:etiology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007668:Kidney / Q000166:cytology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D013398:Sudden Infant Death / Q000453:epidemiology / Q000235:genetics*; D013401:Sugar Alcohol Dehydrogenases / Q000235:genetics* / Q000378:metabolism
C525035:GPD1L protein, human; D005993:Glycerolphosphate Dehydrogenase; D013401:Sugar Alcohol Dehydrogenases