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

Abstract

deficiency (FLD); Hyperchylomicronemia 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 overexpressing 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.

Molecular analysis of three known and one novel LPL variants in patients with type I hyperlipoproteinemia

“…Human wild type LPL cDNA was synthesized and cloned in pcDNA3.1 containing a V5 epitope tag at the C-terminus by GeneArt Gene Synthesis (Thermo Fisher Scientific, Rockford, IL, USA) as previously described [25]. LPL variants were generated by site-directed mutagenesis introducing a single base-pair change in the wild type LPL gene sequence.…”

The Structural Basis for Glycerol Permeation by human AQP7

“…Glycerol, one of the most commonly found polyols in life, is involved in both lipid metabolism and carbohydrate metabolism as energy carrier and molecular backbone. Glycerol is stored in form of triacylglycerols (TAGs) in adipocytes and could be mobilized into free glycerol by lipoprotein lipase upon starvation [1]. The glycerol generated in cytosol is released into circulation and re-absorbed by liver, where it is phosphorylated into glycerol-3-phosphate (G3P) by glycerol kinase and enters the lipid synthesis or glycolytic pathways [2].…”

Rare LPL gene missense mutation in an infant with hypertriglyceridemia

“…1 After synthesis, it is secreted and transported to the luminal surfaces of vascular endothelial cells and embedded in the inner walls of vessels by ion reaction with heparan sulfate proteoglycan or glycosylphosphatidylinositol. 2 The main physiological function of LPL in humans is to hydrolyze chitos an particles in plasma and triglycerides in very low-density lipoproteins, resulting in free fatty acids entering the myocardium and skeletal muscle to undergo oxygenolysis, release energy, or re-synthesize triglycerides stored in adipose tissue. 3 LPL is a rate-limiting enzyme in triglyceride degradation, which plays important roles in lipid metabolism, insulin resistance, and adipocyte differentiation.…”