Medical sciences (Basel, Switzerland) · 2025
Computational Identification of RNF114 nsSNPs with Potential Roles in Psoriasis and Immune Dysregulation.
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Aldoseri Ghalia Mahfod, Alwabran Arwa Ibrahim, Aldoseri Ghanem Mahfod, Aldoseri Mobarak Mahfod, Kamal Ebtihal
Аннотация
BACKGROUND: RNF114 gene encodes an E3 ubiquitin ligase involved in immune signaling and regulation of inflammation. Genetic variants, particularly nonsynonymous single-nucleotide polymorphisms (nsSNPs), may interfere with protein function and cause immune diseases such as psoriasis. Although significant, the structural and functional impact of RNF114 nsSNPs is not well understood.
METHODS: We used comprehensive bioinformatics analyses to predict the functional impact of RNF114 nsSNPs. Deleterious variants were predicted by SIFT, PolyPhen-2, PROVEAN, META-SNP, ESNP&GO, PANTHER, and Alpha-Missense. Protein stability was examined by I-Mutant2.0, and MUpro further contextualized variant effects. Structural modeling was performed by AlphaFold and visualized using UCSF ChimeraX 1.10.1. Additionally, we studied the Conservation using ConSurf and protein-protein interaction by STRING tools.
RESULTS: Among 252 available nsSNPs, three mutations-C49R (rs1600868749), R68C (rs745318334), and R68H (rs758000156)-were predicted to have a deleterious and destabilizing effects on the protein structure by all the tools. All three variants were located in extremely conserved residues and were predicted to significantly destabilize the protein structure. Structural modeling demonstrated disruptions in the RNF114 domain structure. STRING analysis revealed interactions of RNF114 with key immune regulators, and pathway enrichment pointed to roles in NF-κB signaling, ubiquitin-mediated proteolysis, and autoimmune disease pathways.
CONCLUSIONS: In the current study, we predicted three novel, potentially pathogenic RNF114 variants with protein-destabilizing effect that could lead to immune dysregulation.
METHODS: We used comprehensive bioinformatics analyses to predict the functional impact of RNF114 nsSNPs. Deleterious variants were predicted by SIFT, PolyPhen-2, PROVEAN, META-SNP, ESNP&GO, PANTHER, and Alpha-Missense. Protein stability was examined by I-Mutant2.0, and MUpro further contextualized variant effects. Structural modeling was performed by AlphaFold and visualized using UCSF ChimeraX 1.10.1. Additionally, we studied the Conservation using ConSurf and protein-protein interaction by STRING tools.
RESULTS: Among 252 available nsSNPs, three mutations-C49R (rs1600868749), R68C (rs745318334), and R68H (rs758000156)-were predicted to have a deleterious and destabilizing effects on the protein structure by all the tools. All three variants were located in extremely conserved residues and were predicted to significantly destabilize the protein structure. Structural modeling demonstrated disruptions in the RNF114 domain structure. STRING analysis revealed interactions of RNF114 with key immune regulators, and pathway enrichment pointed to roles in NF-κB signaling, ubiquitin-mediated proteolysis, and autoimmune disease pathways.
CONCLUSIONS: In the current study, we predicted three novel, potentially pathogenic RNF114 variants with protein-destabilizing effect that could lead to immune dysregulation.