Genetics research · 2026
Predicting the Impact of Deleterious Single-Nucleotide Polymorphisms in the p47ING1a Isoform of Human ING1 Gene.
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Rafi Md Oliullah, Sarker Md Takim, Sheikh Mohammad Ashik, Das Sowmitro, Halder Sajal Kumar, Islam Md Ashiqul
Аннотация
PURPOSE: The p47ING1a isoform of the ING1 tumor suppressor regulates cellular senescence through Rb-dependent pathways via its plant homeodomain (PHD) zinc-finger, which recognizes the H3K4me3 histone mark. However, the mutational landscape of p47ING1a and the functional consequences of PHD-domain nonsynonymous single-nucleotide polymorphisms (nsSNPs) remain poorly characterized. This study aimed to identify and structurally evaluate the most deleterious nsSNPs in p47ING1a and clarify their potential role in disrupting ING1 tumor-suppressor activity.
METHODS: A total of 347 missense nsSNPs were retrieved from the NCBI dbSNP database and screened using 12 sequence-based computational tools. Variants consistently predicted as deleterious were further evaluated by I-Mutant stability analysis and ConSurf evolutionary conservation profiling. Three-dimensional structural modeling was performed using AlphaFold3, refined through GalaxyRefine, and validated by ERRAT, PROCHECK, and TM-align. Mutation-induced structural and binding effects were assessed using Missense3D, mCSM, and BeAtMuSiC. Post-translational modification sites were predicted via NetPhos 3.1, GPS 3.0, BDM-PUB, and NetOGlyc 4.0. Protein-protein interaction networks were constructed using STRING and Gene MANIA. Pan-cancer expression was analyzed through UALCAN and the Human Protein Atlas.
RESULTS: Twelve computational tools converged on six high-priority variants, namely, C358S, C374G, W378G, F379V, S382L, and R400P. All localized exclusively within the PHD zinc-finger domain, residues 353-402. All six mutations were consistently predicted to destabilize the p47ING1a protein across multiple stability analyses.
CONCLUSIONS: Six nsSNPs in the PHD domain of p47ING1a are predicted to disrupt protein stability, H3K4me3 binding, and Sin3A/HDAC complex interactions, thereby impairing ING1 tumor-suppressor function. These findings provide a computational basis for prioritizing variants for experimental validation through site-directed mutagenesis, chromatin-binding assays, and structure-guided therapeutic targeting of the PHD-H3K4me3 interface.
METHODS: A total of 347 missense nsSNPs were retrieved from the NCBI dbSNP database and screened using 12 sequence-based computational tools. Variants consistently predicted as deleterious were further evaluated by I-Mutant stability analysis and ConSurf evolutionary conservation profiling. Three-dimensional structural modeling was performed using AlphaFold3, refined through GalaxyRefine, and validated by ERRAT, PROCHECK, and TM-align. Mutation-induced structural and binding effects were assessed using Missense3D, mCSM, and BeAtMuSiC. Post-translational modification sites were predicted via NetPhos 3.1, GPS 3.0, BDM-PUB, and NetOGlyc 4.0. Protein-protein interaction networks were constructed using STRING and Gene MANIA. Pan-cancer expression was analyzed through UALCAN and the Human Protein Atlas.
RESULTS: Twelve computational tools converged on six high-priority variants, namely, C358S, C374G, W378G, F379V, S382L, and R400P. All localized exclusively within the PHD zinc-finger domain, residues 353-402. All six mutations were consistently predicted to destabilize the p47ING1a protein across multiple stability analyses.
CONCLUSIONS: Six nsSNPs in the PHD domain of p47ING1a are predicted to disrupt protein stability, H3K4me3 binding, and Sin3A/HDAC complex interactions, thereby impairing ING1 tumor-suppressor function. These findings provide a computational basis for prioritizing variants for experimental validation through site-directed mutagenesis, chromatin-binding assays, and structure-guided therapeutic targeting of the PHD-H3K4me3 interface.