Introduction: Transthyretin (TTR)-related amyloidosis is a life-threatening disease. Currently, several questions about the pathogenic mechanisms of TTR-related amyloidosis remain unanswered.
Methods: We have investigated various TTR-related issues using different in silico approaches.
Results: Using an amino acid similarity-based analysis, we have indicated the most relevant TTR secondary structures in determining mutation impact. Our amyloidogenic propensity analysis of TTR missense substitutions has highlighted a similar pattern for wild-type and mutated TTR amino β acid sequences. However, some mutations present differences with respect to the general distribution. We have identified non-coding variants in cis-regulatory elements of the TTR gene, and our analysis on V122I-related haplotypes has indicated differences in non-coding regulatory variants, suggesting differences among V122I carriers. The analysis of methylation status indicated CpG sites that may affect TTR expression. Finally, our interactive network analysis revealed functional partners of TTR that may play a modifier role in the pathogenesis of TTR-related amyloidosis.
Discussion and conclusion: Our data provided new insights into the pathogenesis of TTR-related amyloidosis that, if they were to be confirmed through experimental investigations, could significantly improve our understanding of the disease.
Keywords: Amyloidogenic propensity; V122I mutation; bioinformatics; cis-regulatory elements; interactive network.