Estudo estrutural in silico de variantes da proteína distrofina relacionadas às distrofias musculares de Duchenne e Becker

Abstract

The advancement of genetic studies and refined methodologies for the diagnosis and treatment of diseases with high genomic complexity has grown exponentially over the past century. Diseases that, no more than 150 years ago, were completely unknown and represented a certain fatality for patients, now benefit from preventive treatments or therapies that provide individuals with a significantly improved quality of life. Becker and Duchenne muscular dystrophies are two of the main dystrophinopaties, diseases caused by mutations in the dystrophin gene, which encodes an intracellular protein with essential structural and mechanical support functions in muscle cells. This study aimed to consult reference databases and theoretical frameworks, combined with in silico bioinformatics methods, in order to expand current knowledge, raise relevant questions, and propose predictions for future research developments in the field. Six clinically relevant dystrophin variants were selected and simulated to assess their structural and phenotypic impacts. Additionally, a theoretical tridimensional homology-based model of the full-length dystrophin protein was developed to further investigate its functional mechanisms, potential active sites, and interactions with other intracellular molecules. Through structural modelling and the simulation of alterations caused by each mutation, it was possible to infer correlations between these molecular changes and the clinical manifestations observed. International databases and computational tools such as the Protein Data Bank, AlphaFold, PyMOL, MODELLER, and Swiss-PdbViewer were employed. The theoretical three-dimensional modeling generated was validated and proved capable of providing valuable insights into dystrophin’s molecular interactions, as well as the structural impacts caused by mutations in its gene. Based on the analysis of the six selected variants, it was possible to infer that the structural and functional consequences of the mutations are directly influenced by their position, particularly depending on which domains are affected. This understanding offers a more in-depth perspective that goes beyond the conventional classification of these diseases based solely on reading frame disruptions or the presence of nonsense variants. Accordingly, the study also briefly discusses the current state of available treatments and future perspectives for improving both therapeutic strategies and research in the field, including the development of novel exon skipping approaches and engineered mini dystrophins.