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- Title
Positional cloning of the combined hyperlipidemia gene Hyplip1.
- Authors
Bodnar, Jackie S.; Chatterjee, Aurobindo; Castellani, Lawrence W.; Ross, David A.; Ohmen, Jeffrey; Cavalcoli, James; Wu, Chenyan; Dains, Katherine M.; Catanese, Joe; Chu, Michael; Sheth, Sonal S.; Charugundla, Kanti; Demant, Peter; West, David B.; de Jong, Pieter; Lusis, Aldons J.
- Abstract
Familial combined hyperlipidemia (FCHL, MIM-144250) is a common, multifactorial and heterogeneous dyslipidemia predisposing to premature coronary artery disease and characterized by elevated plasma triglycerides, cholesterol, or both. We identified a mutant mouse strain, HcB-19/Dem (HcB-19), that shares features with FCHL, including hypertriglyceridemia, hypercholesterolemia, elevated plasma apolipoprotein B and increased secretion of triglyceride-rich lipoproteins. The hyperlipidemia results from spontaneous mutation at a locus, Hyplip1, on distal mouse chromosome 3 in a region syntenic with a 1q21-q23 FCHL locus identified in Finnish, German, Chinese and US families. We finemapped Hyplip1 to roughly 160 kb, constructed a BAC contig and sequenced overlapping BACs to identify 13 candidate genes. We found substantially decreased mRNA expression for thioredoxin interacting protein (Txnip). Sequencing of the critical region revealed a Txnip nonsense mutation in HcB-19 that is absent in its normolipidemic parental strains. Txnip encodes a cytoplasmic protein that binds and inhibits thioredoxin, a major regulator of cellular redox state. The mutant mice have decreased CO[sub 2] production but increased ketone body synthesis, suggesting that altered redox status down-regulates the citric-acid cycle, sparing fatty acids for triglyceride and ketone body production. These results reveal a new pathway of potential clinical significance that contributes to plasma lipid metabolism.
- Subjects
HYPERLIPIDEMIA; GENETIC mutation; TRIGLYCERIDES; GENETICS
- Publication
Nature Genetics, 2002, Vol 30, Issue 1, p110
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng811