Transient infantile hypertriglyceridemia, fatty liver, and hepatic fibrosis caused by mutated GPD1, encoding glycerol-3-phosphate dehydrogenase 1.
The molecular basis for primary hereditary hypertriglyceridemia has been identified in fewer than 5% of cases. Investigation of monogenic dyslipidemias has the potential to expose key metabolic pathways. We describe a hitherto unreported disease in ten individuals manifesting as moderate to severe transient childhood hypertriglyceridemia and fatty liver followed by hepatic fibrosis and the identification of the mutated gene responsible for this condition. We performed SNP array-based homozygosity mapping and found a single large continuous segment of homozygosity on chromosomal region 12q13.12. The candidate region contained 35 genes that are listed in Online Mendelian Inheritance in Man (OMIM) and 27 other genes. We performed candidate gene sequencing and screened both clinically affected individuals (children and adults with hypertriglyceridemia) and also a healthy cohort for mutations in GPD1, which encodes glycerol-3-phosphate dehydrogenase 1. Mutation analysis revealed a homozygous splicing mutation, c.361-1G>C, which resulted in an aberrantly spliced mRNA in the ten affected individuals. This mutation is predicted to result in a truncated protein lacking essential conserved residues, including a functional site responsible for initial substrate recognition. Functional consequences of the mutation were evaluated by measuring intracellular concentrations of cholesterol and triglyceride as well as triglyceride secretion in HepG2 (hepatocellular carcinoma) human cells lines overexpressing normal and mutant GPD1 cDNA. Overexpression of mutant GPD1 in HepG2 cells, in comparison to overexpression of wild-type GPD1, resulted in increased secretion of triglycerides (p = 0.01). This finding supports the pathogenicity of the identified mutation.
Department of Pediatric Genetics, Schneider Children's Medical Center of Israel, Petah Tikva, Israel. basel@post.tau.ac.il
Lina
L
Basel-Vanagaite
Noam
N
Zevit
Adi
A
Har Zahav
Liang
L
Guo
Saj
S
Parathath
Metsada
M
Pasmanik-Chor
Adam D
AD
McIntyre
Jian
J
Wang
Adi
A
Albin-Kaplanski
Corina
C
Hartman
Daphna
D
Marom
Avraham
A
Zeharia
Abir
A
Badir
Oded
O
Shoerman
Amos J
AJ
Simon
Gideon
G
Rechavi
Mordechai
M
Shohat
Robert A
RA
Hegele
Edward A
EA
Fisher
Raanan
R
Shamir
D000293:Adolescent; D017398:Alternative Splicing / Q000235:genetics; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000032:analysis; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+) / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D007223:Infant; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D012720:Severity of Illness Index; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism
D014280:Triglycerides; D002784:Cholesterol; D050536:Glycerol-3-Phosphate Dehydrogenase (NAD+)