Digenic mutations on SCAP and AGXT2 predispose to premature myocardial infarction.
Digenic mutations on SCAP and AGXT2 predispose to premature myocardial infarction.
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SCAP 和 AGXT2 的双基因突变易导致早发心肌梗死
DOI：
10.18632/oncotarget.22045
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发表时间：
2017-11-21
期刊：
影响因子：
--
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Gao Y;Lee C;Song J;Li S;Cui Y;Liu Y;Wang J;Lu F;Chen H
遗传因素在早发心肌梗死(PMI)的发病机制中起着至关重要的作用。然而，目前的研究只解释了心肌梗死的少量遗传风险。在这项研究中，我们从一个PMI家系开始，三名MI患者分别发生在43岁、45岁和53岁。Sanger测序显示该家系中有6名LDLR突变携带者，但只有一人被诊断为PMI，这表明LDLR突变可能不是PMI的原因。通过外显子组测序和生物信息学分析，SCAP和AGXT2的两个变异被鉴定为PMI的潜在致病突变。进一步观察发现，只有符合PMI诊断的患者同时携带两个变异体，而其他MI患者或没有MI的成员仅携带一个变异体。在一个独立的PMI人群中对这两个基因的筛选发现了SCAP上的另一个变异(c.1403T>；C，p.Val468Ala)，这在28,000个东亚人群中是不存在的。进一步，将SCAP和AGXT2的两个变异体导入H293T和EA。用CRISPR-Cas9分别构建了HY926细胞株。功能研究表明，SCAP突变破坏了SCAP-SREBP反馈机制，这可能导致胆固醇合成相关基因的“结构性激活”，而AGXT2突变降低了其转氨酶活性，导致ADMA积聚下调NO的产生。本研究表明SCAP和AGXT2是PMI的潜在致病基因。数字突变携带者可能表现出更严重的表型，即早产儿心肌梗死。
Genetic factors play a vital role in the pathogenesis of premature myocardial infarction (PMI). However, current studies explained only small amounts of genetic risk in MI. In this study, we started from a PMI pedigree with three MI patients occurred at the age of 43, 45 and 53 respectively. Sanger sequencing revealed 6 LDLR mutation carriers in the family, but only one was diagnosed with PMI, indicating that the LDLR mutation may not be the reason for PMI. Upon exome-sequencing and bioinformatics analysis, two variants in SCAP and AGXT2 were identified as potential causative mutation for PMI. Further observation revealed that only patients that meet the diagnosis of PMI harbored two variants meantime, while other MI patients or members with no MI carried no more than one of the variants. Screening of the two genes in an independent PMI population identified another variant on SCAP (c.1403 T>C, p.Val468Ala), which was absent in 28, 000 east-Asian population. Further, the two variants on SCAP and AGXT2 were introduced into H293T and EA. hy926 cell lines respectively utilizing CRISPR-Cas9. Functional study revealed that the SCAP mutation impaired SCAP-SREBP feedback mechanism which may lead to a “constitutive activation” effect of cholesterol synthesis related genes, while the AGXT2 mutation reduced its aminotransferase activity leading to a down-regulation of NO production by ADMA accumulation. This study indicates that SCAP and AGXT2 are potential causative genes for PMI. Digenic mutation carriers may manifest a more severe phenotype, namely premature MI.
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影响因子：
24
作者：
Webb TR;Erdmann J;Stirrups KE;Stitziel NO;Masca NG;Jansen H;Kanoni S;Nelson CP;Ferrario PG;König IR;Eicher JD;Johnson AD;Hamby SE;Betsholtz C;Ruusalepp A;Franzén O;Schadt EE;Björkegren JL;Weeke PE;Auer PL;Schick UM;Lu Y;Zhang H;Dube MP;Goel A;Farrall M;Peloso GM;Won HH;Do R;van Iperen E;Kruppa J;Mahajan A;Scott RA;Willenborg C;Braund PS;van Capelleveen JC;Doney AS;Donnelly LA;Asselta R;Merlini PA;Duga S;Marziliano N;Denny JC;Shaffer C;El-Mokhtari NE;Franke A;Heilmann S;Hengstenberg C;Hoffmann P;Holmen OL;Hveem K;Jansson JH;Jöckel KH;Kessler T;Kriebel J;Laugwitz KL;Marouli E;Martinelli N;McCarthy MI;Van Zuydam NR;Meisinger C;Esko T;Mihailov E;Escher SA;Alver M;Moebus S;Morris AD;Virtamo J;Nikpay M;Olivieri O;Provost S;AlQarawi A;Robertson NR;Akinsansya KO;Reilly DF;Vogt TF;Yin W;Asselbergs FW;Kooperberg C;Jackson RD;Stahl E;Müller-Nurasyid M;Strauch K;Varga TV;Waldenberger M;Wellcome Trust Case Control Consortium;Zeng L;Chowdhury R;Salomaa V;Ford I;Jukema JW;Amouyel P;Kontto J;MORGAM Investigators;Nordestgaard BG;Ferrières J;Saleheen D;Sattar N;Surendran P;Wagner A;Young R;Howson JM;Butterworth AS;Danesh J;Ardissino D;Bottinger EP;Erbel R;Franks PW;Girelli D;Hall AS;Hovingh GK;Kastrati A;Lieb W;Meitinger T;Kraus WE;Shah SH;McPherson R;Orho-Melander M;Melander O;Metspalu A;Palmer CN;Peters A;Rader DJ;Reilly MP;Loos RJ;Reiner AP;Roden DM;Tardif JC;Thompson JR;Wareham NJ;Watkins H;Willer CJ;Samani NJ;Schunkert H;Deloukas P;Kathiresan S;Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
通讯作者：
Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators
DOI：
10.1073/pnas.0500206102
发表时间：
2005-03-01
影响因子：
11.1
作者：
Feramisco, JD;Radhakrishnan, A;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
13.8
作者：
Rodionov, Roman N.;Jarzebska, Natalia;Weiss, Norbert;Lentz, Steven R.
通讯作者：
Lentz, Steven R.
DOI：
10.1007/978-1-4939-1862-1_10
发表时间：
2015-01-01
期刊：
CHROMOSOMAL MUTAGENESIS, SECOND EDITION
影响因子：
--
作者：
Cong, Le;Zhang, Feng
通讯作者：
Zhang, Feng
DOI：
10.1161/atvbaha.112.254078
发表时间：
2012-12-01
影响因子：
8.7
作者：
Caplin, Ben;Wang, Zhen;Leiper, James
通讯作者：
Leiper, James