Clinical and functional studies of two novel variants in the LPL gene in subjects with severe hypertriglyceridemia
Clinical and functional studies of two novel variants in the LPL gene in subjects with severe hypertriglyceridemia
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DOI：
10.1016/j.cca.2018.08.041
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发表时间：
2018-12-01
影响因子：
5
通讯作者：
Khovidhunkit, Weerapan
中科院分区：
文献类型：
--
作者：
Plengpanich, Wanee;Kiateprungvej, Arunrat;Khovidhunkit, Weerapan
背景：最近在高甘油三酯血症 (HTG) 受试者中发现了 LPL 基因中的两个新变异（p.Arg270Gly 和 p.Asp308Glyfs*3）。在本研究中，我们调查了其家族的临床和遗传特征，并在体外检验了这两种变异的功能意义。方法：收集临床和遗传数据。在 cld 细胞中进行定点诱变和瞬时表达。测量脂蛋白脂肪酶 (LPL) 质量和活性。结果：体外研究表明，转染 p.Arg270Gly 变体的细胞培养基中 LPL 质量和活性显着降低。然而，在细胞裂解物中，LPL 质量得以保留，但 LPL 活性降低，表明 LPL 缺陷在于分泌和活性。对于 p.Asp308Glyfs*3 变体，与野生型相比，细胞裂解物中的 LPL 质量相对保留，而培养基中的 LPL 质量减少，尽管不显着。细胞裂解物和转染该变体的细胞培养基中的 LPL 活性显着降低，表明 p.Asp308Glyfs*3 变体可能影响 LPL 的活性，并可能影响 LPL 的分泌。结论：LPL 基因中的这些新变体可能具有分泌和/或活性缺陷的致病性。
Background: Two novel variants (p.Arg270Gly and p.Asp308Glyfs*3) in the LPL gene have recently been identified in subjects with hypertriglyceridemia (HTG). In this study, we investigated clinical and genetic features of their families and examined the functional significance of these two variants in vitro.Methods: Clinical and genetic data were collected. Site-directed mutagenesis and transient expression in cld cells were performed. Lipoprotein lipase (LPL) mass and activity were measured.Results: In vitro studies showed that LPL mass and activity in the media of cells transfected with the p.Arg270Gly variant were significantly reduced. In the cell lysates, however, LPL mass was preserved but LPL activity was reduced, suggesting that the LPL defect was in the secretion and activity. For the p.Asp308Glyfs*3 variant, LPL mass in the cell lysate was relatively preserved compared to that of the wild-type, while LPL mass in the media was decreased albeit not significantly. LPL activities in the cell lysate and in the media of cells transfected with this variant were significantly reduced, suggesting that the p.Asp308Glyfs*3 variant might affect the activity, and possibly, secretion of LPL.Conclusions: These novel variants in the LPL gene were likely pathogenic with the defect in secretion and/or activity.