Bioinformatic analysis of TFR2, HJV, and HFE nonsense mutations in hereditary hemochromatosis: Insights into the pathogenesis of diabetic mellitus and heart failure

Sequence variations in TFR2, HJV, and HFE proteins are causative contributors to a wide range of disorders of iron metabolism, which could result in hereditary hemochromatosis, leading to heart failure and diabetes. Known nonsense variants were retrieved from ClinVar, identifying common variants in diabetes mellitus and heart failure, followed by protein-protein interaction analysis through STRING and Cytoscape for hub genes identification, and then structural modeling through AlphaFold and mutation incorporation through DESMOND Maestro to assess their potential impact on protein function. These mutations have not been previously bioinformatically examined, and thus this research presents the foundational studies for further investigations. The modeling and comparative superimposition analysis of wild and mutant proteins showed that nonsense mutations in TFR2 result in truncated proteins that disrupt crucial domains for iron uptake and transport. Similarly, HJV nonsense mutants, including R63* and C321*, truncate the protein and prevent hepcidin regulation. Nonsense mutations in HFE disrupt conserved regions within MHC class I-like antigen recognition and immunoglobulin C1-set domains, potentially leading to abnormal iron buildup. These findings enhance our understanding of the pathogenic mechanisms of genes with these mutations and highlight the importance of genotyping for predicting the severity of iron overload disorders, aiding effective clinical interventions. HFE mutations primarily affect the MHC class I-like antigen recognition domain, while HJV mutations disrupt hepcidin expression and BMP signaling, contributing to juvenile hemochromatosis. Additionally, previously unreported truncating mutations, such as Q12* and R105*, significantly impair function, exacerbating iron overload and disease progression.