Abstract
Introduction: Congenital heart diseases (CHDs) are structural cardiovascular malformations that arise from abnormal development of the heart during the prenatal life. Mutations in the TBX5 gene, encoding T-box transcription factor, are a major cause of CHD. To evaluate the TBX5 mutations in hotspot exons in sporadic pediatric patients with CHD phenotypes, analytical case/control study performed in an Iranian cohort of unrelated patients with clinical diagnosis of congenital heart malformations. Methods: We investigated TBX5 coding exons 4, 5, 6 and 7 in 95 sporadic patients with CHD phenotypes and compared to 82 healthy controls using PCR-SSCP and DNA sequencing approaches. Results: We report here on a novel and heterozygote Non-sense mutation in exon 5 of TBX5, E128X (G14742T), in two Iranian children. This mutation locates inside the T-box and both of pediatric patients carrying this novel mutation suffer from severe heart malformations. The G14742T mutation leads to the substitution of glutamic acid (E) by stop codon (X) at residue 128, an evolutionarily conserved position in T-box as well as in other species. The non-sense mutation of E128X was predicted to be pathogenic by Mutation Taster and Polyphen software programs. Conclusion: TBX5 E128X mutation results in a translational premature stop. This type of mutation results in a shortened protein that may function improperly and which cannot bind to other transcription factors; therefore, haploinsufficiency of TBX5 protein is presumably causing the severe cardiac malformations in these patients.
Highlights
Congenital heart diseases (CHDs) are structural cardiovascular malformations that arise from abnormal development of the heart during the prenatal life
For first time we found a novel and heterozygous non-sense putative mutation in the exon 5 of TBX5 gene, in two patients (1 and 3 months old infants) with atrial septal defects (ASD) and large ventricular septal defects
This non-sense putative mutation was not founded in the 82 healthy subjects and it was not observe in the SNP databases, suggesting a novel putative mutation in CHD patients
Summary
Congenital heart diseases (CHDs) are structural cardiovascular malformations that arise from abnormal development of the heart during the prenatal life. CHD related mutations are dispersed across all the coding exons of TBX5 gene, the most of them are positioned within the highly evolutionary conserved DNA binding motif (T-box or T-domain), spanning from amino acids 53–241.10, Loss-of function mutations in T-box region on the human chromosome (12q24.1) and haploinsufficiency of TBX5 are the cause of CHD Such nucleotide alterations in T-box affect interactions with the major and minor groove of the target DNA and produce very important heart defects in the developmental pathways of cardiac morphogenesis.[12], In this case/control study, to evaluate the somatic TBX5 mutations in hotspot exons, we have screened 95 sporadic Iranian pediatric patients with CHD phenotypes and compared to 82 healthy matched controls using PCR-SSCP and DNA sequencing approaches
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