The pathogenic potential of the TBX5 gene variants
The analysis of results using the PolyPhen-2 software based on HumDiv
and HumVar database displayed that D111Y and A210G are deleterious
mutations (probably damaging) while L15Q mutation is benign (Table 3). A
mutation is found to be probably damaging if the PolyPhen value exceeds
0.908, possibly damaging if between 0.446 and 0.908 and benign if less
than or equal to 0.446 (Table 3 and Figure 3).
The D111Y
mutation
The D111Y mutation located in exon 4 of TBX5 gene and the T-box
conserved area of its protein. Here, structural stability prediction
showed that D111Y mutation decreases protein stability as well as
PolyPhen-2 analysis revealed its pathogenicity (Table 3 and Figure 3).
This mutation in this study is found with a large defect in the heart
septal (large VASD) and patent ductus arteriosus (PDA). DynaMut analysis
showed this mutation can effect interatomic interactions of the D111Y
mutant residue and can result in destabilization and increase protein
flexibility (Table 3 and Figure 4 A). Also, Granados-Riveron et al was
discovered this mutation in a patient with double outlet right
ventricle, large VASD, and PDA. They by using molecular model of human
TBX5 protein free from nucleic acid based on PDB file 2X6U showed that
there is salt bridge between the D111 and the K126 residues. The D111Y
change disrupts the this salt bridge, as the negatively charged aspartic
acid (D) residue is replaced by an uncharged tyrosine residue (9).