Objective: To identify the novel mutations in the GATA6 gene associated with tetralogy of Fallot (TOF).
Methods: The clinical data and blood samples from 120 unrelated Han Chinese TOF patients and 200 unrelated ethnically matched healthy controls were collected. The coding exons and flanking splice junctions of GATA6 gene were amplified by polymerase chain reaction and sequenced by the technique of di-deoxynucleotide chain termination. The acquired sequences were aligned with those derived from GenBank by the aid of program BLAST to identify the sequence variations. The software ClustalW was applied for the conservation analysis of altered amino acids. The pathogenic probability for each sequence variation was predicted automatically by software MutationTaster.
Results: Three novel heterozygous missense GATA6 mutations were identified in 3 TOF patients. Specifically, the triplet substitutions of CTC for CCC at codon 73, CGC for AGC at codon 364 and GGC for GCC at codon 591, predicting the transitions of proline into leucine at amino acid residue 73 (p.P73L), serine into arginine at amino acid residue 364 (p.S364R) and alanine into glycine at amino acid residue 591 (p.A591G), were detected. None of three mutations was observed in 200 healthy controls. A cross-species alignment of GATA6 encoded protein sequences showed that the mutated amino acids were highly conserved evolutionarily and all 3 mutations were predicted to be pathogenic.
Conclusions: Novel mutations are identified in the GATA6 gene associated with TOF. Such a finding may contribute to an early prophylaxis and therapy of TOF.