AUTHOR=Wang Shuping , Cheng Yiping , Shi Yingzhou , Zhao Wanyi , Gao Ling , Fang Li , Jin Xiaolong , Han Xiaoyan , Sun Qiuying , Li Guimei , Zhao Jiajun , Xu Chao 

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

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.874608

DOI=10.3389/fendo.2022.874608

ISSN=1664-2392

ABSTRACT=Background: Type I hyperlipoproteinemia, characterized by very severe hypertriglyceridemia, is mainly caused by the loss-of-function mutation of lipoprotein lipase (LPL) gene. So far, there have been more than 200 mutations in LPL gene reported and only a limited number of mutations have been evaluated the pathogenesis. 
Objective: To explore the molecular mechanisms underlying the lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia. 
Methods: We conducted the systematic clinical and genetic analysis of two pedigrees with type 1 hyperlipoproteinemia. Post-heparin plasma of all the members was used for the LPL activity analysis. In vitro studies were performed in HEK-293T cells which were transiently transfected with wild type or variant LPL plasmid. Furthermore, the production and activity of LPL was analyzed in cell lysates or culture medium.
Results: Proband 1 developed acute pancreatitis in youth and her serum triglyceride (TG) continued to be at an ultra-high level, although 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 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 respectively in two probands. The post-heparin LPL activity of proband 1 and 2 showed a decrease of 75.09% and 57.29% compared with the control. In vitro studies showed that a substantial reduction in the expression, secretion, or enzyme activity of LPL in all the LPL variants. 
Conclusions: Two novel compound variants of LPL induced the function defects of LPL and caused type I hyperlipoproteinemia.