Clinical and functional studies of two novel variants in the LPL gene in subjects with severe hypertriglyceridemia

Background: Two novel variants (p.Arg270Gly and p.Asp308Glyfs*3) in the LPL gene have recently been identified in subjects with hypertriglyceridemia (HTG). In this study, we investigated clinical and genetic features of their families and examined the functional significance of these two variants in vitro. Methods: Clinical and genetic data were collected. Site-directed mutagenesis and transient expression in cld cells were performed. Lipoprotein lipase (LPL) mass and activity were measured. Results: In vitro studies showed that LPL mass and activity in the media of cells transfected with the p.Arg270Gly variant were significantly reduced. In the cell lysates, however, LPL mass was preserved but LPL activity was reduced, suggesting that the LPL defect was in the secretion and activity. For the p.Asp308Glyfs*3 variant, LPL mass in the cell lysate was relatively preserved compared to that of the wild-type, while LPL mass in the media was decreased albeit not significantly. LPL activities in the cell lysate and in the media of cells transfected with this variant were significantly reduced, suggesting that the p.Asp308Glyfs*3 variant might affect the activity, and possibly, secretion of LPL. Conclusions: These novel variants in the LPL gene were likely pathogenic with the defect in secretion and/or activity.