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Positional cloning of the combined hyperlipidemia gene Hyplip1

Nature Genetics volume 30, pages 110–116 (2002)Cite this article

Abstract

Familial combined hyperlipidemia (FCHL, MIM-144250) is a common, multifactorial and heterogeneous dyslipidemia predisposing to premature coronary artery disease1,2 and characterized by elevated plasma triglycerides, cholesterol, or both3,4. 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 lipoproteins5. 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 families6,7,8. 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.

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Figure 1: Distributions of triglyceride and ketone body levels.
Figure 2: Physical- and fine-mapping of the Hyplip1 locus.
Figure 3: Recombinant animals and their HcB-19 backcross progeny that define the maximal critical interval containing Hyplip1.
Figure 4: Expression and sequence analysis of Txnip.
Figure 5: Metabolic consequences of the Hyplip1 nonsense mutation in Txnip.

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Acknowledgements

This work was supported by grants from the National Institutes of Health and the UCLA Laubisch Fund (A.J.L.) and by a USPHS National Research award (J.B.). We thank S. Charugundla for help in the plasma lipid determinations. We appreciate the excellent technical assistance of Y. Lee, D. San Juan, L. Chen, A. Cairo, S. Tobias, K. Amburgey, D. Civello, J. Choi and Q. Zhang. We also thank O. Iakoubova, H. Sakul and R. Woychik for their expert advice. We appreciate the aid of J. Sinsheimer for the statistical analysis of recombinant animals. We are grateful to R. Davis for his comments on this manuscript. We also thank L. Peltonen, P. Pajukanta, H. Allayee and K. Krass for thoughtful discussion and input. Production of HcB-19/Dem was supported by grants from the Dutch Cancer Foundation and the European Commission (P.D.).

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Authors and Affiliations

  1. Molecular Biology Institute and Departments of Medicine, Human Genetics, and Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, 47-123 CHS

    Jackie S. Bodnar, Lawrence W. Castellani, Michael Chu, Sonal S. Sheth, Kanti Charugundla & Aldons J. Lusis

  2. UCLA School of Medicine, Los Angeles, 90095, California, USA

    Jackie S. Bodnar, Lawrence W. Castellani, Michael Chu, Sonal S. Sheth, Kanti Charugundla & Aldons J. Lusis

  3. Department of Molecular Science, Pfizer Global Research and Development, Ann Arbor Laboratories, Pfizer Inc., Ann Arbor, 48105, Michigan, USA

    Aurobindo Chatterjee, David A. Ross, Jeffrey Ohmen, James Cavalcoli, Chenyan Wu, Katherine M. Dains, Joe Catanese, David B. West & Pieter de Jong

  4. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Peter Demant

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Bodnar, J., Chatterjee, A., Castellani, L. et al. Positional cloning of the combined hyperlipidemia gene Hyplip1. Nat Genet 30, 110–116 (2002). https://doi.org/10.1038/ng811

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