Research Papers:

Digenic mutations on SCAP and AGXT2 predispose to premature myocardial infarction

Yuanfeng Gao, Chongyou Lee, Junxian Song, Sufang Li, Yuxia Cui, Yongzhen Liu, Jie Wang, Fengmin Lu and Hong Chen _

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Oncotarget. 2017; 8:100141-100149. https://doi.org/10.18632/oncotarget.22045

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Yuanfeng Gao1,2,3,*, Chongyou Lee1,2,3,*, Junxian Song1,2,3, Sufang Li1,2,3, Yuxia Cui1,2,3, Yongzhen Liu4, Jie Wang4, Fengmin Lu4 and Hong Chen1,2,3

1Department of Cardiology, Peking University People's Hospital, Xicheng District, Beijing, China

2Beijing Key Laboratory of Early Prediction and Intervention of Acute Myocardial Infarction, Peking University People’ s Hospital, Beijing, China

3Center for Cardiovascular Translational Research, Peking University People’s Hospital, Beijing, China

4Department of Microbiology and Infectious Disease Center, Peking University, Beijing, China

*These authors have contributed equally to this work

Correspondence to:

Hong Chen, email: [email protected]

Keywords: premature myocardial infarction; genetics; exome-sequencing; CRISPR-Cas9; digenic mutation

Received: March 01, 2017     Accepted: July 18, 2017     Published: October 24, 2017


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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