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TBX20 Loss-Of-Function Mutation Contributes to Double Outlet Right Ventricle

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TBX20 Loss-Of-Function Mutation Contributes to Double Outlet Right Ventricle 1058 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 35: 1058-1066, 2015 TBX20 loss-of-function mutation contributes to double outlet right ventricle YUN PAN1*, RUI GENG1*, NING ZHOU1, GUI-FEN ZHENG1, HONG ZHAO1, JUAN WANG2, CUI-MEI ZHAO2, XING-BIAO QIU3, YI-QING YANG3-5 and XING-YUAN LIU1 Departments of 1Pediatrics and 2Cardiology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065; 3Department of Cardiology, 4Cardiovascular Research Laboratory and 5Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China Received November 30, 2014; Accepted January 20, 2015 DOI: 10.3892/ijmm.2015.2077 Abstract. Congenital heart disease (CHD), the most prevalent nant pattern with complete penetrance. The missense mutation birth defect in humans worldwide, is still a leading non-infec- was absent in 400 control chromosomes and the altered amino tious cause of infant morbidity and mortality. Increasing acid was completely conserved evolutionarily across species. evidence demonstrates that genetic risk factors play a key role Functional analysis revealed that mutant TBX20 had a signifi- in the pathogenesis of CHD, and more than 50 genes have cantly diminished transcriptional activity compared with its been linked to various types of CHD. Nevertheless, CHD is wild-type counterpart. To the best of our knowledge, this study a heterogeneous disorder and the genetic components under- is the first to report the association of TBX20 loss-of-function pinning CHD in an overwhelming majority of cases remain mutation with increased susceptibility to DORV in humans, unknown. In the present study, the entire coding exons and which provides novel insight into the molecular mechanisms flanking introns of the TBX20 gene, which codes for a T-box responsible for CHD, suggesting potential implications for the transcription factor essential for the proper development of the antenatal prophylaxis of CHD. heart, were sequenced in a cohort of 146 unrelated patients with CHD. The available relatives of the index patient harboring Introduction an identified mutation and 200 unrelated ethnically matched healthy individuals used as the controls were also genotyped Congenital heart disease (CHD), a structural defect that arises for TBX20. The functional characteristics of the TBX20 muta- from the abnormal formation of the heart or intrathoracic major tion were assayed by using a dual-luciferase reporter assay blood vessel, is the most common form of birth defect in humans, system. As a result, a novel heterozygous TBX20 mutation, affecting approximately 1% of all live births and accounting for p.R143W, was identified in an index patient with double as high as 10% of early miscarriages (1-3). Presently, CHD is outlet right ventricle (DORV). Genetic analyses of the pedi- still the leading non-infectious cause of infant morbidity and gree of the proband revealed that in the family, the mutation mortality worldwide, with approximately 27% of neonates who co-segregated with DORV transmitted in an autosomal domi- die of birth defects having cardiovascular developmental abnor- malities (1). Congenital cardiovascular deformities are usually categorized into 25 distinct clinical types, of which 21 desig- nate specific anatomic or hemodynamic lesions, including atrial septal defect, ventricular septal defect, tetraology of Fallot, Correspondence to: Dr Xing-Yuan Liu, Department of Pediatrics, patent ductus arteriosus, double outlet right ventricle (DORV), Tongji Hospital, Tongji University School of Medicine, 389 Xin Cun endocardial cushion defect, aortic stenosis, coarctation of the Road, Shanghai 200065, P.R. China E-mail: [email protected] aorta, transposition of the great arteries, abnormal pulmonary venous connection, univentricular heart and hypoplastic left Dr Yi-Qing Yang, Department of Cardiology, Cardiovascular heart syndrome (1). Various types of CHD may occur sepa- Research Laboratory and Central Laboratory, Shanghai Chest rately or in combination, giving rise to a degraded quality of Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, life, decreased exercise tolerance, delayed fetal brain develop- Shanghai 200030, P.R. China E-mail: [email protected] ment or brain injury, thromboembolic events, brain abscess or infective endocarditis, hypothyroidism, pulmonary arterial *Contributed equally hypertension or Eisenmenger's syndrome, cardiac dysfunction or heart failure, arrhythmias and even cardiac death (4-27). Key words: congenital heart disease, genetics, transcriptional Although great advances in pediatric cardiovascular care have factor, TBX20, reporter gene allowed most newborns with CHD to survive into adulthood, resulting in an increasing number of adults living with CHD, the surviving patients have a significantly increased incidence of late complications and sudden cardiac death (12-28). PAN et al: TBX20 MUTATION IN DORV 1059 Furthermore, due to the continued improvement of health including an evaluation of individual and medical histories, outcomes for children with CHD, substantial mortality rates a detailed physical examination, 12-lead electrocardiogram, in CHD have shifted away from the young and towards adults, and two-dimensional transthoracic echocardiography with with a steady increase in age at death (29). Hence, CHD has color flow Doppler. A transesophageal echocardiography or imposed a vast economic burden on the families of patients and a cardiac catheterization examination was performed only health care systems, and the socioeconomic burden is expected when there was a strong clinical indication. The diagnosis to be heavier in the future with the increasing number of adults of CHD was made by imaging and/or direct view during with CHD (30). Despite the high prevalence and important cardiac surgery. The patients with known chromosomal abnor- clinical significance, the molecular mechanisms underlying malities or syndromic CHD, such as Turner syndrome, Down CHD in a significant proportion of patients remain poorly syndrome, Di George syndrome, Marfan syndrome and Holt- understood. Oram syndrome were excluded from this study. The controls The etiology of CHD is complex and is associated with comprised 200 unrelated non-CHD individuals from the same both environmental and genetic causes (31-34). Non-genetic geographic area, who were matched to the CHD patients in age, risk factors for CHD mainly involve paternal characteristics gender and ethnicity. and conditions, the use of maternal therapeutic and non-ther- The present study was performed in accordance with the apeutic drugs, and parental environmental exposures (31-33), principles outlined in the Declaration of Helsinki of 1975 while an increasing number of studies on human genetics and as revised in 2008. The study protocol was reviewed and have demonstrated that genetic defects play an important approved by the Ethics Committee of Tongji Hospital, Tongji role in the pathogenesis of CHD, and to date, a long list of University, Shanghai, China (ethical approval number for cases mutations in >60 genes have been linked to isolated CHD or and controls: LL(H)-09-07; date of approval: July 27, 2009). syndromic CHD, where CHD is part of the phenotypes (34-55). Prior to the commencement of the study, all participants or Nevertheless, CHD is a heterogeneous disease, and the genetic their guardians provided written informed consent to the use origin underpinning CHD in an overwhelming majority of of their blood specimens for genetic analysis. patients remains to be unveiled. T-box transcription factors, which are characterized by the Mutational scanning of TBX20. Peripheral venous blood presence of a highly conserved sequence-specific DNA-binding samples were obtained from all the study participants. domain termed the ‘T-box’, have been demonstrated to be Genomic DNA was isolated from the white blood cells of essential for proper organ development (56). To date, at least each participant using the Wizard Genomic DNA Purification 7 members of the T-box gene family, including TBX20 as an kit (Promega, Madison, WI, USA). According to the referen- ancient member of the T-box superfamily, have been shown tial genomic DNA sequence of the TBX20 gene (GenBank to be highly expressed in embryonic heart tissues in humans accession no. NG_015805.1), the primers used to amplify the and vertebrates (56). In developing mouse embryos, TBX20 coding exons and flanking introns of TBX20 by polymerase has been shown to be expressed in cardiac progenitor cells, chain reaction (PCR) were designed as shown in Table I. PCR as well as in the developing myocardium and endothelial cells was performed using HotStar TaqDNA Polymerase (Qiagen, associated with endocardial cushions, the precursor structures Hilden, Germany) on a Verti Thermal Cycler (Applied for the cardiac valves and the atrioventricular septum (57). Biosystems, Foster City, CA, USA) under standard conditions. In mice, the complete ablation of TBX20 has been shown to Both strands of each PCR product were sequenced using a result in the death of embryos at mid-gestation with grossly BigDye® Terminator version 3.1 Cycle Sequencing kit under abnormal heart morphogenesis, while heterozygous TBX20- an ABI PRISM 3130 XL DNA Analyzer (both from Applied knockout mice have shown mild atrial septal anomalies, Biosystems). For an identified sequence variation, the public including an increased prevalence of patent foramen ovale and databases for human sequence variations, including single primum
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