Predicting pathogenic variants in the IHH gene associated with bone development abnormalities: a bioinformatics approach

Abstract Bone development abnormalities are challenging disorders with significant physical and emotional impacts. These abnormalities can stem from genetic or lifestyle factors, with genetic causes presenting ongoing research challenges. This study investigates the Indian hedgehog (Ihh) gene, which is known to be involved in bone formation issues. We analyzed non-synonymous single nucleotide polymorphisms (nsSNPs) in the Ihh gene retrieved from the dbSNP database for their deleterious nature and functional impact using various programs, including PolyPhen-2.0, FATHMM, Panther, SIFT, Provean, Mutation Assessor, and SNPS&GO. The stability of the protein structure was evaluated using Dynamut and I-Mutant 3.0. Out of 436 nsSNPs analyzed, 103 mutations were found to destabilize the protein. Special attention was given to mutations located in domain regions critical for protein function. Native and mutant protein models were predicted using SWISSMODEL, validated with PROCHECK, and compared for RMSD values using PyMOL. Functional impacts were assessed through docking studies with the binding partner using PatchDock. Significant changes in interaction energies and docking scores were observed, suggesting potential effects on protein function. This computational study indicates that these nsSNPs may contribute to bone-related disorders and suggests that the Ihh protein could be a potential drug target for further investigation and improved disease management.