Identification and Characterization of Two Novel Compounds: Heterozygous Variants of Lipoprotein Lipase in Two Pedigrees With Type I Hyperlipoproteinemia.
Identification and Characterization of Two Novel Compounds: Heterozygous Variants of Lipoprotein Lipase in Two Pedigrees With Type I Hyperlipoproteinemia.
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DOI：
10.3389/fendo.2022.874608
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发表时间：
2022
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
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I型高脂蛋白血症主要由脂蛋白脂酶（LPL）基因功能缺失突变引起，其特征为严重的高脂血症。到目前为止，已经报道了200多个LPL基因突变，而只有有限数量的突变被评估为发病机制。本研究旨在探讨两个1型高脂蛋白血症家系脂蛋白脂酶缺乏的分子机制。我们对两个1型高脂蛋白血症家系进行了系统的临床和遗传学分析。所有成员的肝素后血浆均用于LPL活性分析。在用野生型或变体LPL质粒瞬时转染的HEK-293 T细胞中进行体外研究。此外，在细胞裂解物或培养基中分析LPL的产生和活性。先证者1在年轻时发生急性胰腺炎，尽管应用了各种降脂药物，她的血清甘油三酯（TG）仍持续处于高水平。先证者2在9个月大时被诊断为1型高脂蛋白血症，治疗后其血清TG水平轻度升高。两个新的复合杂合型LPL（c.3G>C，p.M1？和c.835_836delCT，p. L279 Vfs *3，c.188C>T，p. Ser 63 Phe和c.662T>C，p. Ile 221 Thr）在两个先证者中被鉴定出来。先证者1和2的肝素后LPL活性分别比对照组降低72.22 ± 9.46%（p<0.01）和54.60 ± 9.03%（p<0.01）。体外研究显示LPL变体中LPL的表达或酶活性显著降低。两个新的复合杂合子变异体LPL诱导缺陷的表达和功能的LPL和引起I型高脂蛋白血症。这些变体的功能表征与假定的LPL突变体活性一致。
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. This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia. 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. 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. 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.
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DOI：
10.1016/s0003-3995(01)01037-1
发表时间：
2001-01-01
期刊：
ANNALES DE GENETIQUE
影响因子：
--
作者：
Gilbert, B;Rouis, M;Laplaud, PM
通讯作者：
Laplaud, PM
DOI：
10.1073/pnas.1820171116
发表时间：
2019-05-21
影响因子：
11.1
作者：
Arora, Rishi;Nimonkar, Amitabh V.;Trauger, John W.
通讯作者：
Trauger, John W.
影响因子：
5
作者：
Plengpanich, Wanee;Kiateprungvej, Arunrat;Khovidhunkit, Weerapan
通讯作者：
Khovidhunkit, Weerapan
影响因子：
5.3
作者：
Evans, D.;Arzer, J.;Beil, F. U.
通讯作者：
Beil, F. U.
影响因子：
15.9
作者：
HENDERSON, HE;MA, Y;HAYDEN, MR
通讯作者：
HAYDEN, MR