4-Phenylbutyrate rescues trafficking incompetent mutant alpha-galactosidase A without restoring its functionality.
Fabry disease is a lysosomal storage disorder caused by deficiency of alpha-galactosidase A. Most mutant enzyme is catalytically active but due to misfolding retained in the endoplasmic reticulum. We have tested 4-phenylbutyrate for its potential to rescue various trafficking incompetent mutant alpha-galactosidase A. Although we found that the trafficking blockade for endoplasmic reticulum-retained mutant alpha-Gal A was released, neither a mature enzyme was detectable in transgenic mice fibroblasts nor a reversal of lysosomal Gb3 storage in fibroblasts from Fabry patients could be observed. Because of lack of functionality of rescued mutant alpha-galactosidase A, 4-phenylbutyrate seems to be of limited use as a chemical chaperone for Fabry disease.
Yam
Gary Hin-Fai
GH
Division of Cell and Molecular Pathology, Department of Pathology, University of Zurich, CH-8091 Zürich, Switzerland.
Roth
Jürgen
J
Zuber
Christian
C
D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000795:Fabry Disease / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010654:Phenylbutyrates / Q000008:administration & dosage / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology*; D000519:alpha-Galactosidase / Q000235:genetics / Q000378:metabolism*
D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; D000519:alpha-Galactosidase