Genetic analysis of the TBX1 gene promoter in ventricular septal defects.
Congenital heart disease (CHD) is the most common birth defects in humans. The genetic causes for CHD remain largely unknown. T-box transcription factor 1 (TBX1), a dosage-sensitive regulator, plays a critical role in the heart development. Mutations in the coding regions of TBX1 gene have been associated to 22q11 deletion syndrome with cardiac defects and isolated CHD cases, including ventricular septal defect (VSD). To date, TBX1 gene promoter region has not been analyzed and reported in CHD patients. We hypothesized that the sequence variants within TBX1 gene promoter region may change TBX1 levels and mediate CHD development. In this study, the promoter regions of TBX1 gene were genetically and functionally analyzed in 280 VSD patients and 267 healthy controls. Two novel heterozygous variants, g.4353C>T and g.4510A>C, were found in two VSD patients, but in none of controls. The single-nucleotide polymorphism-rs41260844, g.4199T>C, was found more frequent in VSD patients than controls (P < 0.01). Functional analyses revealed that these sequence variants significantly enhanced transcriptional activities of TBX1 gene promoter. Therefore, the sequence variants within TBX1 gene promoter may contribute to the VSD etiology by altering the expression levels of TBX1 gene. Pharmaceutical or genetic manipulation of TBX1 gene expression may provide a novel personalized therapy to prevent and treat late cardiac complications for the adult CHD patients carrying these variants.
Shandong Provincial Key Laboratory of Cardiac Disease Diagnosis and Treatment, Jining Medical University Affiliated Hospital, Jining Medical University, Jining, Shandong, China.
Haihua
H
Wang
Dongfeng
D
Chen
Liming
L
Ma
Haihong
H
Meng
Yumei
Y
Liu
Wen
W
Xie
Shuchao
S
Pang
Bo
B
Yan
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D057809:HEK293 Cells; D006345:Heart Septal Defects, Ventricular / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; 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
D020825:T-Box Domain Proteins; C108625:TBX1 protein, human