4-Phenylbutyrate rescues trafficking incompetent mutant α-galactosidase A without restoring its functionality

Fabry disease is a lysosomal storage disorder caused by deficiency of α-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 α-galactosidase A. Although we found that the trafficking blockade for endoplasmic reticulum-retained mutant α-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 α-galactosidase A, 4-phenylbutyrate seems to be of limited use as a chemical chaperone for Fabry disease.