title: Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors: Piero
authors: P
authors: Pingitore
authors: Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy.
authors: Saverio Massimo
authors: SM
authors: Lepore
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors: Carlo
authors: C
authors: Pirazzi
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors: Rosellina Margherita
authors: RM
authors: Mancina
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors: Benedetta Maria
authors: BM
authors: Motta
authors: Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
authors: Luca
authors: L
authors: Valenti
authors: Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Ullevaal, Oslo, Norway.
authors: Knut Erik
authors: KE
authors: Berge
authors: Department of Nutrition, Institute for Basic Medical Sciences, University of Oslo, Oslo, Norway; Lipid Clinic, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Kjetil
authors: K
authors: Retterstøl
authors: Unit for Cardiac and Cardiovascular Genetics, Department of Medical Genetics, Oslo University Hospital, Ullevaal, Oslo, Norway.
authors: Trond P
authors: TP
authors: Leren
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors: Olov
authors: O
authors: Wiklund
authors: Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden. Electronic address: stefano.romeo@wlab.gu.se.
authors: Stefano
authors: S
authors: Romeo
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008072:Hyperlipoproteinemia Type I / Q000097:blood / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D055815:Young Adult
chemical_list: D008071:Lipoprotein Lipase
keywords: Familial lipoprotein lipase deficiency (FLD); Hyperchylomicronemia; Hypertriglyceridemia; Missense and frameshift mutations; Type 1 hyperlipoproteinemia