In silico analysis of the deleterious nsSNPs (missense) in the homeobox domain of human HOXB13 gene responsible for hereditary prostate cancer

5 years ago

In silico analysis of the deleterious nsSNPs (missense) in the homeobox domain of human HOXB13 gene responsible for hereditary prostate cancer

Gopalakrishnan Chandrasekaran, Vinoth-Kumar Lakshmanan, Je-Jung Lee, Taek Won Kang, Kwangsung Park, Dong Deuk Kwon, Eu Chang Hwang

The human HOXB13 gene encodes a transcription factor containing a DNA-binding homeobox domain and a HoxA13 N-terminal domain. SNP is considered to be the primary genetic cause for hereditary prostate cancer (PCa). The study of functional nsSNPs would give an insight into the exact cause underlying the onset of hereditary PCa and possible methodologies for the cure or early management of the disease. Several in silico tools were used to screen and map the deleterious nsSNPs to the protein structure for predicting the structure–function effects. Among the 23 homeobox nsSNPs, sift predicted 20, whereas PolyPhen, panther, and provean predicted 21 nsSNP's as deleterious. W63R, D244N, K239Q, P222R, K218R, and G216C were found to have higher energy values than the native 2CRA. The RMSD value showed increased deviation for T253P(2.53 Å), P222R(2.27 Å), G216C(2.15 Å), K218R(1.66 Å), and K239Q(1.62 Å). The I-Mutant showed increase in the stability of R258C, S254T, S250L, K239Q, and Q227E. Ramachandran plot showed mutants P222R, G216C, W263R, and K218R having drastically unfavorable pattern of amino acid residues. The presence of these mutations may result in the altered structure and function of the transcription factor; however, the exact mechanism and pathology of those predicted nsSNPs should further be validated by in vivo experiments and population-based studies. In silico analysis and screening of the nsSNPs present in the DNA-binding domain (homeobox) of human HOXB13 gene is of crucial importance, since nsSNPs are known to be the prime cause for hereditary prostate cancer. Further, in silico protein mutation studies and subsequent validation by Ramachandran plot revealed P222R, G216C, W263R, and K218R to render serious damaging effects on the HOXB13 protein structure, stability, and function. However, the exact mechanism and pathology of these nsSNPs should be studied in depth in vitro/ in vivo.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12938