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This version published online on October 9, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-0594
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Submitted on March 18, 2009
Accepted on August 5, 2009

Novel LMF1 Nonsense Mutation in a Patient with Severe Hypertriglyceridemia

Angelo B. Cefalù, Davide Noto, Maria Luisa Arpi, Fen Yin, Rossella Spina, Hannele Hilden, Carlo M. Barbagallo, Antonio Carroccio, Patrizia Tarugi, Sebastiano Squatrito, Riccardo Vigneri, Marja-Riitta Taskinen, Miklós Péterfy, and Maurizio R. Averna*

Department of Clinical Medicine and Emerging Diseases (A.B.C., D.N., R.S., C.M.B., A.C., M.R.A.), University of Palermo, 90127 Palermo, Italy; Department of Internal Medicine (M.L.A., S.S., R.V.), Endocrinology Unit, University of Catania, 95125 Catania, Italy; Department of Medicine (F.Y., M.P.), University of California, Los Angeles, Los Angeles, California 90095; Lipid Research Laboratory (F.Y., M.P.), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073; Medical Genetics Institute (F.Y., M.P.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Department of Medicine (H.H., M.-R.T.), Helsinki University Hospital, FI-00029 Helsinki, Finland; and Department of Biomedical Sciences (P.T.), University of Modena and Reggio Emilia, 41100 Modena, Italy

* To whom correspondence should be addressed. E-mail: avernam{at}unipa.it.

Context: Lipase maturation factor 1 (LMF1) gene is a novel candidate gene in severe hypertriglyceridemia. Lmf1 is involved in the maturation of lipoprotein lipase (LPL) and hepatic lipase in endoplasmic reticulum. To date only one patient with severe hypertriglyceridemia and related disorders was found to be homozygous for a nonsense mutation in LMF1 gene (Y439X).

Objective: The objective of the study was to investigate LMF1 gene in hypertriglyceridemic patients in whom mutations in LPL, APOC2, and APOA5 genes had been excluded.

Results: The resequencing of LMF1 gene led to the discovery of a novel homozygous nonsense mutation in one patient with severe hypertriglyceridemia and recurrent episodes of pancreatitis. The mutation causes a G>A substitution in exon 9 (c.1395G>A), leading to a premature stop codon (W464X). LPL activity and mass were reduced by 76 and 50%, respectively, compared with normolipidemic controls. The proband over the years has shown a good response to treatment. The proband's son, heterozygous for the W464X, shows normal plasma triglyceride levels.

Conclusions: We identified the second novel pathogenic mutation in LMF1 gene in a patient with severe hypertriglyceridemia. LPL deficiency in our patient was milder than in the carrier of the Y439X previously described.






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