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Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia

Abstract

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.

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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.

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Acknowledgements

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).

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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.

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Correspondence to Miklós Péterfy or Mark H Doolittle.

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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). https://doi.org/10.1038/ng.2007.24

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