Newly identified missense mutation reduces lipoprotein lipase activity in Taiwanese patients with hypertriglyceridemia

Lipoprotein lipase (LPL) plays a crucial role in the regulation of lipoprotein metabolism by hydrolyzing the core triglycerides of circulating chylomicrons and very low-density lipoprotein. Deficiency in this enzyme usually results in disturbances in lipid levels. To understand the molecular defect that leads to a functional deficiency of LPL in patients with hypertriglyceridemia, we looked for mutations of the LPL gene by means of single-strand conformation polymorphism (SSCP) analysis and direct DNA sequencing in 24 patients. A single base C→G substitution in codon 252 of the LPL gene, encoding a change of a leucine to a valine residue in the mature protein, was found in three women who had hypertriglyceridemia and recurrent pancreatitis. Two of these patients, who were homozygous for the L252V mutation, had variable and occasionally severe hypertriglyceridemia with undetectable or very low LPL activities, respectively. The third woman was heterozygous for this mutation. All three patients had poor postheparin LPL activity. Site-directed mutagenesis experiments provided in vitro evidence that the mutation of codon 252 was responsible for the loss of LPL activity. In conclusion, we identified a novel LPL mutation that results in decreased LPL activity in Taiwanese patients with hypertriglyceridemia. The assessment of a causative link between the mutation and hyperlipidemia awaits further studies.