Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia


Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity1,2,3. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis4,5,6. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL)7,8,9, caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER)10. Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia4,11,12.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Phenotype of combined lipase deficiency.
Figure 2: Expression of Tmem112 (Lmf1) rescues lipase deficiency in cld/cld cells.
Figure 3: Identification of the cld mutation.
Figure 4: Lmf1 is an ER membrane protein that belongs to a conserved protein family.
Figure 5: Hypertriglyceridemia and combined lipase deficiency in an individual homozygous for a nonsense mutation (Y439X) in LMF1.

Accession codes




  1. Austin, M.A., Hokanson, J.E. & Edwards, K.L. Hypertriglyceridemia as a cardiovascular risk factor. Am. J. Cardiol. 81, 7B–12B (1998).

    Article  CAS  Google Scholar 

  2. Ginsberg, H.N. & Stalenhoef, A.F. The metabolic syndrome: targeting dyslipidaemia to reduce coronary risk. J. Cardiovasc. Risk 10, 121–128 (2003).

    Article  Google Scholar 

  3. Pejic, R.N. & Lee, D.T. Hypertriglyceridemia. J. Am. Board Fam. Med. 19, 310–316 (2006).

    Article  Google Scholar 

  4. Henderson, H.E. et al. Lipoprotein lipase activity is decreased in a large cohort of patients with coronary artery disease and is associated with changes in lipids and lipoproteins. J. Lipid Res. 40, 735–743 (1999).

    CAS  PubMed  Google Scholar 

  5. Mead, J.R., Irvine, S.A. & Ramji, D.P. Lipoprotein lipase: structure, function, regulation, and role in disease. J. Mol. Med. 80, 753–769 (2002).

    Article  CAS  Google Scholar 

  6. Merkel, M., Eckel, R.H. & Goldberg, I.J. Lipoprotein lipase: genetics, lipid uptake, and regulation. J. Lipid Res. 43, 1997–2006 (2002).

    Article  CAS  Google Scholar 

  7. Paterniti, J.R. Jr, Brown, W.V., Ginsberg, H.N. & Artzt, K. Combined lipase deficiency (cld): a lethal mutation on chromosome 17 of the mouse. Science 221, 167–169 (1983).

    Article  CAS  Google Scholar 

  8. Peterfy, M., Mao, H.Z. & Doolittle, M.H. The cld mutation: narrowing the critical chromosomal region and selecting candidate genes. Mamm. Genome 17, 1013–1024 (2006).

    Article  CAS  Google Scholar 

  9. Reue, K. & Doolittle, M.H. Naturally occurring mutations in mice affecting lipid transport and metabolism. J. Lipid Res. 37, 1387–1405 (1996).

    CAS  PubMed  Google Scholar 

  10. Briquet-Laugier, V., Ben-Zeev, O., White, A. & Doolittle, M.H. cld and lec23 are disparate mutations that affect maturation of lipoprotein lipase in the endoplasmic reticulum. J. Lipid Res. 40, 2044–2058 (1999).

    CAS  PubMed  Google Scholar 

  11. Elbein, S.C. et al. Molecular screening of the lipoprotein lipase gene in hypertriglyceridemic members of familial noninsulin-dependent diabetes mellitus families. J. Clin. Endocrinol. Metab. 79, 1450–1456 (1994).

    CAS  PubMed  Google Scholar 

  12. Helio, T., Palotie, A., Sane, T., Tikkanen, M.J. & Kontula, K. No evidence for linkage between familial hypertriglyceridemia and apolipoprotein B, apolipoprotein C–III or lipoprotein lipase genes. Hum. Genet. 94, 271–278 (1994).

    Article  CAS  Google Scholar 

  13. Blanchette-Mackie, E.J. et al. Effect of the combined lipase deficiency mutation (cld/cld) on ultrastructure of tissues in mice. Diaphragm, heart, brown adipose tissue, lung, and liver. Lab. Invest. 55, 347–362 (1986).

    CAS  PubMed  Google Scholar 

  14. Davis, R.C., Ben-Zeev, O., Martin, D. & Doolittle, M.H. Combined lipase deficiency in the mouse. Evidence of impaired lipase processing and secretion. J. Biol. Chem. 265, 17960–17966 (1990).

    CAS  PubMed  Google Scholar 

  15. Scow, R.O., Schultz, C.J., Park, J.W. & Blanchette-Mackie, E.J. Combined lipase deficiency (cld/cld) in mice affects differently post-translational processing of lipoprotein lipase, hepatic lipase and pancreatic lipase. Chem. Phys. Lipids 93, 149–155 (1998).

    Article  CAS  Google Scholar 

  16. Boonyaratanakornkit, J., Chew, A., Ryu, D.D., Greenhalgh, D.G. & Cho, K. Murine endogenous retroviruses and their transcriptional potentials. Mamm. Genome 15, 914–923 (2004).

    Article  Google Scholar 

  17. Maksakova, I.A. et al. Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet. 2, e2 (2006).

    Article  Google Scholar 

  18. Sonnhammer, E.L., Eddy, S.R. & Durbin, R. Pfam: a comprehensive database of protein domain families based on seed alignments. Proteins 28, 405–420 (1997).

    Article  CAS  Google Scholar 

  19. Helenius, A. & Aebi, M. Roles of N-linked glycans in the endoplasmic reticulum. Annu. Rev. Biochem. 73, 1019–1049 (2004).

    Article  CAS  Google Scholar 

  20. Ben-Zeev, O. & Doolittle, M.H. Maturation of hepatic lipase. Formation of functional enzyme in the endoplasmic reticulum is the rate-limiting step in its secretion. J. Biol. Chem. 279, 6171–6181 (2004).

    Article  CAS  Google Scholar 

  21. Ben-Zeev, O., Mao, H.Z. & Doolittle, M.H. Maturation of lipoprotein lipase in the endoplasmic reticulum. Concurrent formation of functional dimers and inactive aggregates. J. Biol. Chem. 277, 10727–10738 (2002).

    Article  CAS  Google Scholar 

  22. Okamoto, Y. et al. Hypertriglyceridemia caused by the autoantibody to lipases for plasma lipoproteins: a case report. J. Atheroscler. Thromb. 2, 66–69 (1995).

    Article  CAS  Google Scholar 

  23. Ranganathan, S. & Kern, P.A. The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes. J. Endocrinol. 172, 155–162 (2002).

    Article  CAS  Google Scholar 

  24. Boedeker, J.C., Doolittle, M.H. & White, A.L. Differential effect of combined lipase deficiency (cld/cld) on human hepatic lipase and lipoprotein lipase secretion. J. Lipid Res. 42, 1858–1864 (2001).

    CAS  PubMed  Google Scholar 

  25. Peterfy, M., Phan, J. & Reue, K. Alternatively spliced lipin isoforms exhibit distinct expression pattern, subcellular localization, and role in adipogenesis. J. Biol. Chem. 280, 32883–32889 (2005).

    Article  CAS  Google Scholar 

  26. Boberg, J. & Carlson, L.A. Determination of heparin-induced lipoprotein lipase activity in human plasma. Clin. Chim. Acta 10, 420–427 (1964).

    Article  CAS  Google Scholar 

Download references


We thank K. Artzt and D. Barlow for DNA samples from heterozygous mice with various t haplotypes; all human subjects that participated in this study; and M. Eeva, E. Nikkola and I. Movsesyan for technical assistance. This work was supported by grants from the National Institutes of Health (HL28481 to M.P., M.H.D. and P.P.; HL082762 to P.P.; KL2-RR024130 to B.E.A.), the American Heart Association (0430180N to P.P.; 0655195Y to C.R.P.; A102799 to B.E.A.), the Joseph Drown Foundation, Donald Yellon, the Mildred V. Strouss Charitable Trust, the Fondation Leducq and the Hellman Family Award. D.W.-V. was supported by a grant from the National Human Genome Research Institute (T32 HG02536).

Author information

Authors and Affiliations



M.P. and M.H.D. designed the study and contributed to the writing of the paper; M.P. carried out molecular characterizations of the cld mutation and immunocytochemistry; O.B.-Z. carried out phenotype rescue experiments and cld mouse phenotype assessment; H.Z.M. assisted in molecular characterizations; D.W.-V. and P.P. sequenced LMF1 exons in all human subjects; B.E.A., C.R.P., P.H.F., J.P.K. and M.J.M. recruited human subjects and carried out their phenotype assessment; K.R. provided key intellectual input and contributed to the writing of this paper.

Corresponding authors

Correspondence to Miklós Péterfy or Mark H Doolittle.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Table 1 (PDF 84 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Péterfy, M., Ben-Zeev, O., Mao, H. et al. Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. Nat Genet 39, 1483–1487 (2007).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing