Abstract
Three-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsive to such treatment. We find that predicted ΔΔG of mutation is higher on average for variants unresponsive to treatment, in the case of datasets for both Fabry disease and Pompe disease, in line with previous findings. Using both a single decision tree and an advanced machine learning approach based on the larger Fabry dataset, we correctly predict responsiveness of three Gaucher disease variants, and we provide predictions for untested variants. Many variants are predicted to be responsive to treatment, suggesting that drug-based treatments may be effective for a number of variants in Gaucher disease. In our analysis, we observe dependence on a topological feature reporting on contact arrangements which is likely connected to the order of folding of protein residues, and we provide a potential justification for this observation based on steady-state cellular kinetics.
Highlights
One mechanism by which a missense mutation can exert a pathogenic effect is by destabilizing the protein in which it is located, leading to deficiency of the protein, not just its enzymatic activity [1,2,3,4,5]
Pharmacological chaperones are small molecule drugs that bind to proteins to help stabilize the folded state
One set of diseases for which this treatment has been effective is the lysosomal storage disorders, which are caused by defective lysosomal enzymes
Summary
One mechanism by which a missense mutation can exert a pathogenic effect is by destabilizing the protein in which it is located, leading to deficiency of the protein, not just its enzymatic activity [1,2,3,4,5]. Pharmacological chaperones have become popular as potential treatments for several diseases, including some lysosomal storage disorders, over the past 20 years, and the drug Migalastat (with the commercial name Galafold) based on this approach, has been approved for treatment of Fabry disease [14,15,16]. The drug binds the protein as an inhibitor, assisting folding in the Endoplasmic Reticulum. This follows an initial observation that the product and inhibitor galactose, of which Migalastat is an analog, improves activity and patient condition, it is not a feasible therapeutic due to the high required dose [9,17]. For lysosomal storage disorders of appropriate genotype, oral pharmacological chaperone treatment can replace or supplement intravenous enzyme replacement treatment, which is expensive and does not cross the blood-brain barrier
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