Positional cloning of the combined hyperlipidemia gene Hyplip1

• Published in: Nature genetics Vol. 30; no. 1; pp. 110 - 116
• Main Authors: Lusis, Aldons J, 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.01.2002
• Subjects: Animals; Animals, Congenic; Biological and medical sciences; Carbon Dioxide - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cholesterol; chromosome 3; Chromosomes, Artificial, Bacterial - genetics; Chromosomes, Human, Pair 1 - genetics; Citric Acid Cycle - genetics; Cloning; Cloning, Molecular; Codon - genetics; Codon, Nonsense; Complications and side effects; Contig Mapping; Cosmids - genetics; Cricetinae; Crosses, Genetic; Diagnosis; Disease Models, Animal; Energy Metabolism - genetics; Exons - genetics; Fatty acids; Fatty Acids - metabolism; Fundamental and applied biological sciences. Psychology; Gene mutations; Genes. Genome; Genetic aspects; Genotype & phenotype; Haplotypes; Haplotypes - genetics; Humans; Hybrid Cells; Hyperlipidemia; Hyperlipidemia, Familial Combined - genetics; Hyperlipidemia, Familial Combined - metabolism; Hyplip1 gene; Ketone Bodies - biosynthesis; Methods; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Mutation; Oxidation-Reduction; Physiological aspects; Plasma; thioredoxin-interacting protein; Thioredoxins - antagonists & inhibitors; Triglycerides; Triglycerides - blood; Txnip gene; United States; Los Angeles California; Netherlands; California; Ann Arbor Michigan; United States > US; Premature; Plasma; Rodentia; Cardiovascular disease; Metabolic diseases; Hyperlipoproteinemia; Triglyceride; Coronary heart disease; Enzymopathy; Cholesterol; Strain; Vascular disease; Vertebrata; Mammalia; Hypercholesterolemia; Gene; Mouse; Hypertriglyceridemia; Atherosclerosis; Hyperlipemia; Dyslipemia
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng811

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 fine-mapped 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 CO2 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.