In silico analysis of mutations in PITX3 gene

PITX3 belongs to a class of heomeodomain transcription factors involved in the development of dopaminergic neurons and ocular lens. Despite a great degree of homology, the mutation in human and mouse Pitx3 gene exhibit differences in the range and extent of phenotypic effects. The current study was designed to predict the effect of mutations in the mouse and human PITX3 gene using in silico tools. We used publically available bioinformatics tools to identify the secondary structure, functional domains, three-dimensional structure and DNA binding residues. Analysis of functional domains in the PITX3 revealed a lack of OAR domain in the G219fs mutation and in the mouse eyeless mutation. There was no difference in the functional motifs of the S13N and K111E mutation compared to the wild-type PITX3. However, an additional helix-turn-helix (HTH) domain is predicted in K111E mutation. Comparison of three-dimensional structures of the wild-type and mutant proteins did not show significant differences except 220delG. The eyeless mouse mutant protein exhibited a very different structure compared to the wild-type mouse Pitx3. Our results indicate that three-dimensional structure of the protein is a good predictor of the in vitro and in vivo behavior of the PITX3 protein and provides guidelines for performing the functional assays of the mutant proteins.