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

Plengpanich, Wanee; Kiateprungvej, Arunrat; Charoen, Supannika; Khovidhunkit, Weerapan

doi:10.1016/j.cca.2018.08.041

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…The LPL protein consists of a large N-terminal domain (amino acid residues 1–315) and a small C-terminal domain (amino acid residues 316–448). The N-terminal domain contains the catalytic center, active site region, substrate-binding site, and heparin-binding site ( 19 , 20 ). In addition to participating in the binding of heparin to the substrate, the C-terminal domain has been considered to be critical to the formation and stability of the LPL head and tail non-covalent homodimers ( 21 , 22 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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BackgroundType 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.ObjectiveThis study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia.MethodsWe 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.ResultsProband 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.ConclusionsTwo 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.

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Section: Discussionmentioning

confidence: 99%