Identifying the impact of structurally and functionally high-risk nonsynonymous SNPs on human patched protein using in-silico approach

• Published in: Gene reports 2021-06, Vol.23, p.101097, Article 101097
• Main Authors: Joshi, Jigna S., Badgujar, Nutan V., Patel, Hitarth V., Raval, Apexa P., Tarapara, Bhoomi V., Shah, Franky D.
• Format: Article
• Language: English
• Subjects: Disease-associated polymorphism; In-silico analysis; nsSNPs; PTCH1
• ISSN: 2452-0144; 2452-0144
• DOI: 10.1016/j.genrep.2021.101097

Human PTCH1 is a negative receptor of Hedgehog (HH) signaling required to sustain cancer stem-like cells (CSCs) in a tumor microenvironment to drive tumor growth. If mutations are present in the PTCH1 gene results in the autocrine signaling and switches pathway on even in the absence of HH ligand. Further functional reduction in native PTCH1 protein may result in the impaired function of the protein. To identify the functionally deleterious SNPs in human PTCH1 protein. Various computational tools like SIFT, PolyPhen2, PROVEAN, SNAP2, SNPs&GO, PhD-SNP, I-Mutant, iPTREE-STAB and MUpro were used to predict most deleterious SNPs of PTCH1. ConSurf and NCBI conserved domain search tool was used to find conserved domain. Post translational modification sites were predicted using ModPred. SPARKS-X was used to generate 3D structure of the PTCH1 protein. In human PTCH1 gene, a total of 60 nonsynonymous SNPs (nsSNPs) were identified to be deleterious or non-tolerable by SIFT. Further, out of 60 nsSNPs, P298L, V907G, R1024H, R134Q, W235R, D259A, and R570Q were predicted to be present in the conserved domain of PTCH1 protein and potentially damaging by all the prediction tools. Amongst them, P298, V907 and R570 were predicted as a site for post-translational modifications (PTM) while R1024 to be involved in a ligand-binding residue. Current study demonstrated that most deleterious nsSNPs found is arginine to histidine at position 1024 responsible for disease occurrence which might be helpful to eliminate CSCs in a tumor bulk. [Display omitted] •The HH-PTCH is involved in the progression of many types of cancers.•The consequences of nsSNPs found on PTCH1 was analysed using computational tools.•P298L, V907G, R1024H, R134Q, W235R, D259A, R570Q found deleterious nsSNPs on PTCH1.•P298, V907, R134 & R570 found to be involved in post translational modifications.•R1024 was predicted as a ligand-binding site residue.