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=13

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=<sec><title>Background</title><p>Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the <italic>lipoprotein lipase</italic> (<italic>LPL</italic>) gene. To date, more than 200 mutations in the <italic>LPL</italic> gene have been reported, while only a limited number of mutations have been evaluated for pathogenesis.</p></sec><sec><title>Objective</title><p>This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia.</p></sec><sec><title>Methods</title><p>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. <italic>In vitro</italic> studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant <italic>LPL</italic> plasmids. Furthermore, the production and activity of LPL were analyzed in cell lysates or culture medium.</p></sec><sec><title>Results</title><p>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 <italic>LPL</italic> (c.3G&gt;C, p. M1? and c.835_836delCT, p. L279Vfs*3, c.188C&gt;T, p. Ser63Phe and c.662T&gt;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&lt;0.01) and 54.60 ± 9.03% (p&lt;0.01), respectively, compared with the control. <italic>In vitro</italic> studies showed a substantial reduction in the expression or enzyme activity of LPL in the <italic>LPL</italic> variants.</p></sec><sec><title>Conclusions</title><p>Two novel compound heterozygous variants of <italic>LPL</italic> 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 <italic>LPL</italic> mutant activity.</p></sec>