A Heterozygous LMF1 Gene Mutation (c.1523C>T), Combined With an LPL Gene Mutation (c.590G>A), Aggravates the Clinical Symptoms in Hypertriglyceridemia.
A Heterozygous LMF1 Gene Mutation (c.1523C>T), Combined With an LPL Gene Mutation (c.590G>A), Aggravates the Clinical Symptoms in Hypertriglyceridemia.
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DOI：
10.3389/fgene.2022.814295
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发表时间：
2022
影响因子：
3.7
通讯作者：
Zheng H
中科院分区：
文献类型：
--
作者：
Guo D;Zheng Y;Gan Z;Guo Y;Jiang S;Yang F;Xiong F;Zheng H
高脂血症是动脉粥样硬化性心血管疾病（ASCVD）和急性胰腺炎的重要原因。家族性高甘油三酯血症通常由参与甘油三酯代谢的基因突变引起。在此，我们调查了一个中国高胆固醇血症家系的致病基因突变，并在体外评估了其功能意义。全外显子组测序（WES）结果显示，该例重度高脂血症先证者LPL基因第5外显子存在错义突变（c.590G > A），LMF 1基因第10外显子存在错义突变（c.1523C > T）。Polyphen-2保守性分析表明，LMF 1蛋白的508位点和LPL蛋白的197位点在不同物种间高度保守。I-TASSER分析表明LMF 1 c.1523C > T突变和LPL c.590G > A突变改变了蛋白质的三级结构。在用携带LMF 1 c.1523C > T突变的质粒转染的293 T细胞中观察到mRNA和蛋白质表达的降低。亚细胞定位结果表明，野生型（WT）和突变型LMF 1蛋白定位于细胞质。在细胞培养基和细胞裂解物中，这些LMF 1和LPL基因突变均导致LPL质量减少。此外，LMF 1和LPL基因突变的组合与其对LPL浓度的单独影响相比显著降低了LPL水平。临床和体外实验结果均提示，该患者的严重高脂血症是由LMF 1和LPL突变的双杂合性引起的双基因起源。
Hypertriglyceridemia is an important contributor to atherosclerotic cardiovascular disease (ASCVD) and acute pancreatitis. Familial hypertriglyceridemia is often caused by mutations in genes involved in triglyceride metabolism. Here, we investigated the disease-causing gene mutations in a Chinese family with hypertriglyceridemia and assessed the functional significance in vitro. Whole-exome sequencing (WES) was performed revealing that the severe hypertriglyceridemic proband carried a missense mutation (c.590G > A) in exon 5 of the LPL gene, as well as a missense mutation (c.1523C > T) in exon 10 of the LMF1 gene. Conservation analysis by Polyphen-2 showed that the 508 locus in the LMF1 protein and 197 locus in the LPL protein were highly conserved between different species. I-TASSER analysis indicated that the LMF1 c.1523C > T mutation and the LPL c.590G > A mutation changed the tertiary structure of the protein. A decrease in mRNA and protein expression was observed in 293T cells transfected with plasmids carrying the LMF1 c.1523C > T mutation. Subcellular localization showed that both wild-type (WT) and mutant LMF1 protein were localized at the cell cytoplasm. In the cell medium and cell lysates, these LMF1 and LPL gene mutations both caused a decreased LPL mass. Moreover, the combination of LMF1 and LPL gene mutations significantly decreased LPL levels compared to their individual effects on the LPL concentration. Both the clinical and in vitro data suggest that severe hypertriglyceridemia was of digenic origin caused by LMF1 and LPL mutation double heterozygosity in this patient.
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影响因子：
5.3
作者：
Catapano, Alberico L;Graham, Ian;Zamorano, Jose Luis
通讯作者：
Zamorano, Jose Luis
影响因子：
3.7
作者：
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通讯作者：
Pearce, Elizabeth N
影响因子：
4.4
作者：
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通讯作者：
Di Taranto, Maria Donata
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影响因子：
29
作者：
Sha H;Sun S;Francisco AB;Ehrhardt N;Xue Z;Liu L;Lawrence P;Mattijssen F;Guber RD;Panhwar MS;Brenna JT;Shi H;Xue B;Kersten S;Bensadoun A;Péterfy M;Long Q;Qi L
通讯作者：
Qi L
影响因子：
4.4
作者：
Cefalu, Angelo B.;Spina, Rossella;Averna, Maurizio R.
通讯作者：
Averna, Maurizio R.