title: Novel and functional variants within the TBX18 gene promoter in ventricular septal defects.
abstract: Congenital heart disease (CHD) is the most common birth defect in humans. Genetic causes for CHD remain largely unknown. T-box transcription factor 18 (TBX18) gene is expressed in the developing heart, including myocardium of the left ventricle and interventricular septum. Epicardial cells expressing TBX18 gene contribute to the cardiac fibroblast and smooth muscle cells. We speculated that the DNA sequence variants (DSVs) within TBX18 gene promoter may mediate CHD development by affecting TBX18 levels and the cardiac gene regulatory network. In this study, we genetically and functionally analyzed the TBX18 gene promoter in patients with ventricular septal defects (VSD) (n = 326) and ethnic-matched healthy controls (n = 327). Three novel heterozygous DSVs (g.85474435del, g.85474418C>T, and g.85473965C>G) and one single nucleotide polymorphism (g.85474871C>T, rs77693245) were identified in VSD patients, but none in the controls. Functional analysis revealed that the DSVs (g.85474871C>T, g.85474435del, and g.85473965C>G) significantly decreased the transcriptional activities of the TBX18 gene promoter. The effect of DSV (g.85474418C>T) on the TBX18 gene promoter was marginal, but not significant. Therefore, the DSVs within the TBX18 gene promoter identified in VSD patients may be involved in the VSD etiology.
authors.affiliation: Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and Treatment, Jining Medical University Affiliated Hospital, Jining Medical University, 79 Guhuai Road, Jining, 272029, Shandong, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Ma
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.forename: Yumei
authors.initials: Y
authors.lastname: Liu
authors.forename: Shuchao
authors.initials: S
authors.lastname: Pang
authors.forename: Wenhui
authors.initials: W
authors.lastname: Huang
authors.forename: Bo
authors.initials: B
authors.lastname: Yan
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006345:Heart Septal Defects, Ventricular / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020825:T-Box Domain Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D020825:T-Box Domain Proteins; C523796:Tbx18 protein, human