Abhinav Pradhan, Li Yan-Jie, Huang Ri-Tai, Liu Xing-Yuan, Gu Jia-Ning, Yang Chen-Xi, Xu Ying-Jia, Wang Juan, Yang Yi-Qing
Department of Cardiology, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China.
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, P.R. China.
Exp Ther Med. 2024 Jan 8;27(2):91. doi: 10.3892/etm.2024.12379. eCollection 2024 Feb.
Tetralogy of Fallot (TOF) is the most prevalent cyanotic congenital heart pathology and causes infant morbidity and mortality worldwide. GATA-binding protein 4 (GATA4) serves as a pivotal transcriptional factor for embryonic cardiogenesis and germline mutations are causally linked to TOF. However, the effects of somatic mutations on the pathogenesis of TOF remain to be ascertained. In the present study, sequencing assay of was performed utilizing genomic DNA derived from resected heart tissue specimens as well as matched peripheral blood specimens of 62 patients with non-familial TOF who underwent surgical treatment for TOF. Sequencing of was also performed using the heart tissue specimens as well as matched peripheral venous blood samples of 68 sporadic cases who underwent heart valve displacement because of rheumatic heart disorder and the peripheral venous whole blood samples of 216 healthy subjects. The function of the mutant was explored by dual-luciferase activity analysis. Consequently, a new mutation, NM_002052.5:c.708T>G;p.(Tyr236*), was found in the heart tissue of one patient with TOF. No mutation was detected in the heart tissue of the 68 cases suffering from rheumatic heart disorder or in the venous blood samples of all 346 individuals. mutant failed to transactivate its target gene, myosin heavy chain 6. Additionally, this mutation nullified the synergistic transactivation between GATA4 and T-box transcription factor 5 or NK2 homeobox 5, two genes causative for TOF. Somatic mutation predisposes TOF, highlighting the significant contribution of somatic variations to the molecular pathogenesis underpinning TOF.
法洛四联症（TOF）是最常见的青紫型先天性心脏病，在全球范围内导致婴儿发病和死亡。GATA结合蛋白4（GATA4）是胚胎心脏发生的关键转录因子，种系突变与TOF有因果关系。然而，体细胞突变对TOF发病机制的影响仍有待确定。在本研究中，利用来自62例接受TOF手术治疗的非家族性TOF患者的切除心脏组织标本以及匹配的外周血标本中的基因组DNA进行测序分析。还使用68例因风湿性心脏病接受心脏瓣膜置换的散发病例的心脏组织标本以及匹配的外周静脉血样本和216例健康受试者的外周静脉全血样本进行测序。通过双荧光素酶活性分析探索突变体的功能。结果，在1例TOF患者的心脏组织中发现了一个新的突变，NM_002052.5:c.708T>G;p.(Tyr236*)。在68例风湿性心脏病患者的心脏组织或所有346例个体的静脉血样本中均未检测到突变。突变体无法激活其靶基因肌球蛋白重链6。此外，该突变消除了GATA4与T盒转录因子5或NK2同源盒5（两个导致TOF的基因）之间的协同激活作用。体细胞突变易患TOF，突出了体细胞变异对TOF分子发病机制的重要贡献。
