Abstract
Lipoprotein lipase (LPL) is widely expressed in skeletal muscles, cardiac muscles as well as adipose tissue and involved in the catabolism of triglyceride. Herein we have systematically characterized two novel loss-of-function mutations in LPL from a Chinese family in which afflicted members were manifested by severe hypertriglyceridemia and recurrent pancreatitis. DNA sequencing revealed that the proband was a heterozygote carrying a novel c.T928C (p.C310R) mutation in exon 6 of the LPL gene. Another member of the family was detected to be a compound heterozygote who along with the c.T928C mutation also carried a novel missense mutation c.A1187T (p.E396V) in exon 8 of the LPL gene. Furthermore, COS-1 cells were transfected with lentiviruses containing the mutant LPL genes. While C310R markedly reduced the overall LPL protein level, COS-1 cells carrying E396V or double mutations contained similar overall LPL protein levels to the wild-type. The specific activity of the LPL mutants remained at comparable magnitude to the wild-type. However, few LPL were detected in the culture medium for the mutants, suggesting that both mutations caused aberrant triglyceride catabolism. More specifically, E396V and double mutations dampened the transport of LPL to the cell surface, while for the C310R mutation, reducing LPL protein level might be involved. By characterizing these two novel LPL mutations, this study has expanded our understanding on the pathogenesis of familial hypertriglyceridemia (FHTG).
Highlights
Severe hypertriglyceridemia refers to fasting triglyceride exceeding 1000 mg/dL (11.3 mmol/L) [1]
We have systematically characterized two novel loss-of-function mutations in Lipoprotein lipase (LPL) from a Chinese family in which afflicted members were manifested by severe hypertriglyceridemia and recurrent pancreatitis
These mutations are mostly concentrated in lipoprotein lipase (LPL) which catabolize triglyceride in non-hepatic tissues, apolipoprotein C-II (APOC2) which acts as an essential LPL activator, apolipoprotein A-V (APOA5) which stabilize the lipoprotein–LPL complex, lipase maturation factor 1 (LMF1) which is involved in the folding and expression of LPL, and glycosylphosphatidylinositolanchored high density lipoprotein-binding protein 1 (GPIHBP1) which mediates the transmembrane transport of LPL and the binding between lipoprotein and LPL [6, 7]
Summary
Severe hypertriglyceridemia refers to fasting triglyceride exceeding 1000 mg/dL (11.3 mmol/L) [1]. Primary hypertriglyceridemia is mainly caused by loss-of-function genetic defects leading to blunted lipolysis of chylomicrons and accumulation of triglyceride. These mutations are mostly concentrated in lipoprotein lipase (LPL) which catabolize triglyceride in non-hepatic tissues, apolipoprotein C-II (APOC2) which acts as an essential LPL activator, apolipoprotein A-V (APOA5) which stabilize the lipoprotein–LPL complex, lipase maturation factor 1 (LMF1) which is involved in the folding and expression of LPL, and glycosylphosphatidylinositolanchored high density lipoprotein-binding protein 1 (GPIHBP1) which mediates the transmembrane transport of LPL and the binding between lipoprotein and LPL [6, 7]. LPL defects with autosomal recessive transmission accounts for more than 90% of FHTG [8]
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