Dataset Information

Digenic mutations on SCAP and AGXT2 predispose to premature myocardial infarction.

ABSTRACT: 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.

SUBMITTER: Gao Y

PROVIDER: S-EPMC5725008 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Digenic mutations on <i>SCAP</i> and <i>AGXT2</i> predispose to premature myocardial infarction.

Gao Yuanfeng Y Lee Chongyou C Song Junxian J Li Sufang S Cui Yuxia Y Liu Yongzhen Y Wang Jie J Lu Fengmin F Chen Hong H

Oncotarget 20171024 59

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 bioinformati ...[more]

PMID: 29245966

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Project description:BACKGROUND:ENAM mutations cause autosomal dominant or recessive amelogenesis imperfecta (AI) and show a dose effect: enamel malformations are more severe or only penetrant when both ENAM alleles are defective. METHODS:Whole exome sequences of recruited AI probands were initially screened for mutations in known AI candidate genes. Sanger sequencing was used to confirm sequence variations and their segregation with the disease phenotype. The co-occurrence of ENAM and LAMA3 mutations in one family raised the possibility of digenic inheritance. Enamel formed in Enam+/+ Ambn+/+ , Enam+/- , Ambn+/- , and Enam+/- Ambn+/- mice was characterized by dissection and backscattered scanning electron microscopy (bSEM). RESULTS:ENAM mutations segregating with AI in five families were identified. Two novel ENAM frameshift mutations were identified. A single-nucleotide duplication (c.395dupA/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous LAMA3 mutation (c.1559G>A/p.Cys520Tyr) that cosegregated with both the AI phenotype and the ENAM mutation. In mice, Ambn+/- maxillary incisors were normal. Ambn+/- molars were also normal, except for minor surface roughness. Ambn+/- mandibular incisors were sometimes chalky and showed minor chipping. Enam+/- incisor enamel was thinner than normal with ectopic mineral deposited laterally. Enam+/- molars were sometimes chalky and rough surfaced. Enam+/- Ambn+/- enamel was thin and rough, in part due to ectopic mineralization, but also underwent accelerated attrition. CONCLUSION:Novel ENAM mutations causing AI were identified, raising to 22 the number of ENAM variations known to cause AI. The severity of the enamel phenotype in Enam+/- Ambn+/- double heterozygous mice is caused by composite digenic effects. Digenic inheritance should be explored as a cause of AI in humans.

Project description:IntroductionAdvancing understanding of key factors that determine the magnitude of the hemostatic response may facilitate the identification of individuals at risk of generating an occlusive thrombus as a result of an atherothrombotic event such as an acute Myocardial Infarction (MI). While fibrinogen levels are a recognized risk factor for MI, the association of thrombotic risk with other coagulation proteins is inconsistent. This is likely due to the complex balance of pro- and anticoagulant factors in any individual.MethodsWe compared measured levels of pro- and anticoagulant proteins in plasma from 162 patients who suffered an MI at an early age (MI <50 y) and 186 age- and gender-matched healthy controls with no history of CAD. We then used the measurements from these individuals as inputs for an established mathematical model to investigate how small variations in hemostatic factors affect the overall amplitude of the hemostatic response and to identify differential key drivers of the hemostatic response in male and female patients and controls.ResultsPlasma from the MI patients contained significantly higher levels of Tissue Factor (P = 0.007), the components of the tenase (FIX and FVIII; P < 0.0001 for both) and the prothrombinase complexes (FX; P = 0.003), and lower levels of Tissue Factor Pathway Inhibitor (TFPI; P = 0.033) than controls. The mathematical model, which generates time-dependent predictions describing the depletion, activation, and interaction of the main procoagulant factors and inhibitors, identified different patterns of hemostatic response between MI patients and controls, and additionally, between males and females. Whereas, in males, TF, FVIII, FIX, and the inhibitor TFPI contribute to the differences seen between case and controls, and in females, FII, FVIII, and FIX had the greatest influence on the generation of thrombin. We additionally show that further donor stratification may be possible according to the predicted donor response to anticoagulant therapy.ConclusionsWe suggest that modeling could be of value in enhancing our prediction of risk of premature MI, recurrent risk, and therapeutic efficacy.

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Digenic mutations on SCAP and AGXT2 predispose to premature myocardial infarction.

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Digenic mutations on <i>SCAP</i> and <i>AGXT2</i> predispose to premature myocardial infarction.

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