Preventing Lysosomal Storage Dysorders by Preimplantation Genetic Diagnosis

Abstract

The growing number of information and databases generated from the different omics has allowed the generation of global reconstructions of metabolic networks of several organisms. In this study, we used the global reconstruction of the human metabolic network (Recon 1) to model the metabolic alterations produced by the disruption of the glycosaminoglycans (GAG) degradation pathways. Simulations were done using COBRA Toolbox 2.0 at MATLAB r2010b. The objective function of the model was setup to GAG degradation, and twenty-five reactions involved in the degradation of heparan, dermatan, keratan, and chondroitin sulfate were independently silenced. After reaction silencing, models were optimized and flux balance analysis (FBA) carried out. Results were compared against normal model, and processed by principal components analysis (PCA). While silencing of reactions causing in MPS I, II, IIIA and IIIC did not produced any change in FBA (r2=1), a significant change was observed for other reactions silencing, showing the impairment of 400 to 500 reactions in comparison to the normal model. On the other side, it is noteworthy that there were 303 reactions that were altered only once in all models, which might guide the search of specific markers for some of these diseases. Likewise, it was observed that 64% of the studied reactions share in common 213 impaired reactions, which could be targets in the search for new drugs. These preliminary results show the potential of metabolic networks reconstructions for the study of Mucopolysaccharidosis and other GAG related diseases.