Compound heterozygosity of Leu252Val and Leu252Arg causing lipoprotein lipase deficiency in a Chinese patient with hypertriglyceridemia

BACKGROUND: We investigated lipoprotein lipase (LPL) gene mutations in a Chinese male with severe hypertriglyceridemia and recurrent pancreatitis. METHODS: We screened for LPL sequence mutation in the LPL gene in this patient, his relatives and 160 unrelated hypertriglyceridaemic subjects. We determined the postheparin plasma LPL activity of subjects carrying a LPL mutation and studied the in vitro expression of mutant LPL in COS-1 cells. RESULTS: The proband was found to be a compound heterozygote for a novel Leu252Val and a reported Leu252Arg mutation in the LPL gene. He had low plasma levels of postheparin LPL activity and mass. The two mutations segregated independently in his family. In vitro expression analysis showed that Leu252Arg abolished both the catalytic function and secretion of LPL, while Leu252Val abolished the catalytic function but only reduced secretion by about half. We have also detected heterozygous Leu252Val and Leu252Arg mutations each in one hypertriglyceridaemic individual. CONCLUSION: These results indicated that the leucine 252 is critical for the catalytic activity and secretion of LPL. Why the substitution by valine instead of arginine resulted only in a partial suppression of LPL secretion, remains to be investigated. Leu252Val and Leu252Arg are the likely cause of hypertriglyceridemia in these subjects because of their deleterious effects on LPL activity or secretion. Leu252Val/Leu252Arg is the first compound heterozygous mutation known to occur in the same codon of the LPL gene. So far they are found only in Chinese.