Identification and Characterization of Two Novel Compounds: Heterozygous Variants of in Two Pedigrees With Type I Hyperlipoproteinemia.

Background: Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the () gene. To date, more than 200 mutations in the gene have been reported, while only a limited number of mutations have been evaluated for pathogenesis.

Objective: This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia.

Methods: We conducted a systematic clinical and genetic analysis of two pedigrees with type 1 hyperlipoproteinemia. Postheparin plasma of all the members was used for the LPL activity analysis. studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant plasmids. Furthermore, the production and activity of LPL were analyzed in cell lysates or culture medium.

Results: Proband 1 developed acute pancreatitis in youth, and her serum triglycerides (TGs) continued to be at an ultrahigh level, despite the application of various lipid-lowering drugs. Proband 2 was diagnosed with type 1 hyperlipoproteinemia at 9 months of age, and his serum TG levels were mildly elevated with treatment. Two novel compound heterozygous variants of (c.3G>C, p. M1? and c.835_836delCT, p. L279Vfs*3, c.188C>T, p. Ser63Phe and c.662T>C, p. Ile221Thr) were identified in the two probands. The postheparin LPL activity of probands 1 and 2 showed decreases of 72.22 ± 9.46% (p<0.01) and 54.60 ± 9.03% (p<0.01), respectively, compared with the control. studies showed a substantial reduction in the expression or enzyme activity of LPL in the variants.

Conclusions: Two novel compound heterozygous variants of induced defects in the expression and function of LPL and caused type I hyperlipoproteinemia. The functional characterization of these variants was in keeping with the postulated mutant activity.