2011
DOI: 10.1186/1750-1172-6-66
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Therapy of Fabry disease with pharmacological chaperones: from in silico predictions to in vitro tests

Abstract: BackgroundFabry disease is a rare disorder caused by a large variety of mutations in the gene encoding lysosomal alpha-galactosidase. Many of these mutations are unique to individual families. Fabry disease can be treated with enzyme replacement therapy, but a promising novel strategy relies on small molecules, so called "pharmacological chaperones", which can be administered orally. Unfortunately only 42% of genotypes respond to pharmacological chaperones.ResultsA procedure to predict which genotypes responsi… Show more

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Cited by 33 publications
(38 citation statements)
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“…These MASS plots show that certain disease mutations are spread through the aggregation spectrum, suggesting that they might affect the intrinsic aggregation propensity of the protein as well as reduce its thermodynamic stability, which could lead to protein aggregation. tion, and using aggregation propensity as a classifier we can predict DGJ response with an accuracy that is equivalent to the most performing predictor algorithms using sequence information from ␣-Gal homologs (17,18). This demonstrates that the aggregation propensity of ␣-Gal mutants is an important determinant for DGJ response, although it is clear that other factors certainly also participate.…”
Section: Discussionmentioning
confidence: 86%
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“…These MASS plots show that certain disease mutations are spread through the aggregation spectrum, suggesting that they might affect the intrinsic aggregation propensity of the protein as well as reduce its thermodynamic stability, which could lead to protein aggregation. tion, and using aggregation propensity as a classifier we can predict DGJ response with an accuracy that is equivalent to the most performing predictor algorithms using sequence information from ␣-Gal homologs (17,18). This demonstrates that the aggregation propensity of ␣-Gal mutants is an important determinant for DGJ response, although it is clear that other factors certainly also participate.…”
Section: Discussionmentioning
confidence: 86%
“…Structural analysis reveals that the most disruptive mutants are on average associated with the most severe forms of the disease, and they are also on average the least responsive to DGJ treatment (43,44). However, it remains very difficult to predict DGJ response from structure only, as only 40% of the nonresponsive mutants can be identified in this manner (17,18). Clearly, thermodynamic destabilization and thus severity of misfolding alone are not sufficient to characterize the therapeutic response (16).…”
Section: Discussionmentioning
confidence: 99%
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“…The cells were transfected with individual plasmids containing mutant AGAL-encoding ORF using the LipofectAMINE2000 cationic lipid reagent in suspension [36]. …”
Section: Methodsmentioning
confidence: 99%
“…Tests on transfected mutants were carried out as described in [36]. Briefly: cell lysates (1–2 microliters) were added to 38 microliters of AGAL assay buffer (sodium citrate 27 mM-sodium phosphate dibasic 46 mM, 4-methylumbelliferyl-alpha-D-galactopyranoside 5 mM and N-acetyl-D-galactosamine 100 mM, pH 4.5) and incubated for 0.5–1 h at 37°C.…”
Section: Methodsmentioning
confidence: 99%