Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia

Piero Pingitore, Saverio Massimo Lepore, Carlo Pirazzi, Rosellina Margherita Mancina, Benedetta Maria Motta, Luca Valenti, Knut Erik Berge, Kjetil Retterstøl, Trond P. Leren, Olov Wiklund, Stefano Romeo

Research output: Contribution to journalArticlepeer-review


Background: Type 1 hyperlipoproteinemia is a rare autosomal recessive disorder most often caused by mutations in the lipoprotein lipase (LPL) gene resulting in severe hypertriglyceridemia and pancreatitis. Objectives: The aim of this study was to identify novel mutations in the LPL gene causing type 1 hyperlipoproteinemia and to understand the molecular mechanisms underlying the severe hypertriglyceridemia. Methods: Three patients presenting classical features of type 1 hyperlipoproteinemia were recruited for DNA sequencing of the LPL gene. Pre-heparin and post-heparin plasma of patients were used for protein detection analysis and functional test. Furthermore, in vitro experiments were performed in HEK293 cells. Protein synthesis and secretion were analyzed in lysate and medium fraction, respectively, whereas medium fraction was used for functional assay. Results: We identified two novel mutations in the LPL gene causing type 1 hyperlipoproteinemia: a two base pair deletion (c.765_766delAG) resulting in a frameshift at position 256 of the protein (p.G256TfsX26) and a nucleotide substitution (c.1211 T > G) resulting in a methionine to arginine substitution (p.M404 R). LPL protein and activity were not detected in pre-heparin or post-heparin plasma of the patient with p.G256TfsX26 mutation or in the medium of HEK293 cells over-expressing recombinant p.G256TfsX26 LPL. A relatively small amount of LPL p.M404 R was detected in both pre-heparin and post-heparin plasma and in the medium of the cells, whereas no LPL activity was detected. Conclusions: We conclude that these two novel mutations cause type 1 hyperlipoproteinemia by inducing a loss or reduction in LPL secretion accompanied by a loss of LPL enzymatic activity.

Original languageEnglish
Pages (from-to)816-823
Number of pages8
JournalJournal of Clinical Lipidology
Issue number4
Publication statusPublished - 2016


  • Familial lipoprotein lipase deficiency (FLD)
  • Hyperchylomicronemia
  • Hypertriglyceridemia
  • Missense and frameshift mutations
  • Type 1 hyperlipoproteinemia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Endocrinology, Diabetes and Metabolism
  • Internal Medicine
  • Nutrition and Dietetics


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