Title : Identification and Characterization of Two Novel Compounds: Heterozygous Variants of Lipoprotein Lipase in Two Pedigrees With Type I Hyperlipoproteinemia - Wang_2022_Front.Endocrinol.(Lausanne)_13_874608 |
Author(s) : Wang S , Cheng Y , Shi Y , Zhao W , Gao L , Fang L , Jin X , Han X , Sun Q , Li G , Zhao J , Xu C |
Ref : Front Endocrinol (Lausanne) , 13 :874608 , 2022 |
Abstract :
BACKGROUND: Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the lipoprotein lipase (LPL) gene. To date, more than 200 mutations in the LPL 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. In vitro studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant LPL 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 LPL (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. In vitro studies showed a substantial reduction in the expression or enzyme activity of LPL in the LPL variants. CONCLUSIONS: Two novel compound heterozygous variants of LPL 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 LPL mutant activity. |
PubMedSearch : Wang_2022_Front.Endocrinol.(Lausanne)_13_874608 |
PubMedID: 35923617 |
Gene_locus related to this paper: human-LPL |
Mutation | S63F_human-LPL M1I_human-LPL L279VfsX3_human-LPL I221T_human-LPL |
Gene_locus | human-LPL |
Disease | Hyperlipoproteinemia TypeI |
Wang S, Cheng Y, Shi Y, Zhao W, Gao L, Fang L, Jin X, Han X, Sun Q, Li G, Zhao J, Xu C (2022)
Identification and Characterization of Two Novel Compounds: Heterozygous Variants of Lipoprotein Lipase in Two Pedigrees With Type I Hyperlipoproteinemia
Front Endocrinol (Lausanne)
13 :874608
Wang S, Cheng Y, Shi Y, Zhao W, Gao L, Fang L, Jin X, Han X, Sun Q, Li G, Zhao J, Xu C (2022)
Front Endocrinol (Lausanne)
13 :874608