Wilms’s Tumor Gene Mutations: Loss of Tumor Suppresser Function: A Bioinformatics Study

Introduction: Mutation in the Wilms’s Tumor (WT1) gene product has been detected in both sporadic and familial cases suggesting that alteration in WT1 may disrupt its normal function. The study aims to find the protagonist amino acid in WT1 proteins by mutating these residues with other amino acids. Material and Methods: The 3D modeling approach by MODELLER 4 was utilized to build a homology of WT1 proteins. Quality of the WT1 model was verified by predicting 10 models of WT1 and hence selecting the best one. Stereochemistry of model was evaluated by PROCHECK. Mutational studies were done by WHAT IF. Five human WT1 mutations were modeled which were Lys371→Ala371, Ser415→Ala415, Cys416→Ala416, His434→Asp434 and His434→Arg434. Result: Based on active side of WT1 protein and its role in DNA binding mutation. No significant change was observed when Lys371 was mutated to Ala371, Ser415 was mutated to Ala415. Significant change was observed in Cys416 mutated to Ala416. In mutant Ala416, loss of coordination with the metal ion Zn was also predicted. In case of Mutants His434→Asp434, there was a loss of coordination of metal ion (Zn203) with mutant Asp434. In case of mutant His434→Arg434, there was a loss of Zn203 coordination with Arg434. His434 does not interact directly with any DNA base, whereas mutated Arg434 is predicted to interact directly with DNA base. Conclusion: It is concluded that mutation of amino acid residue Cys416→Ala416, His434→Asp434 and His434→Arg434 may lose the proto-oncogenic function of WT1.