Misprocessing of α-Galactosidase A, Endoplasmic Reticulum Stress, and the Unfolded Protein Response

Abstract

Background Classic Fabry disease is caused by GLA mutations that result in loss of enzymatic activity of alpha-galactosidase A, lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic Fabry disease, patients have some preserved alpha-galactosidase A activity and a milder disease course. Heterozygous females may also be affected. While Fabry disease pathogenesis has been mostly attributed to catalytic deficiency of mutated alpha-galactosidase A, lysosomal storage and impairment of lysosomal functions, other pathogenic factors may contribute, especially in non-classic Fabry disease. Methods We characterized the genetic, clinical, biochemical, molecular, cellular and organ pathology correlates of the p.L394P alpha-galactosidase A variant that was identified initially in six individuals with kidney failure by the Czech national screening program for Fabry disease and by further screening in additional 24 family members. Results Clinical findings in affected males revealed a milder clinical course with ∼15% residual alpha-galactosidase A activity with normal plasma lyso-globotriaosylceramide levels and abnormally low ratio of these values. None of the four available kidney biopsies showed lysosomal storage. Laboratory investigations documented intracellular retention of mutated alpha-galactosidase A with resulting endoplasmic reticulum stress and the unfolded protein response, which were alleviated with BRD4780, a small molecule clearing misfolded proteins from the early secretory compartment. We observed similar findings of endoplasmic reticulum stress and unfolded protein response in five kidney biopsies with several other classic and non-classic Fabry disease missense alpha-galactosidase A variants. Conclusions We identified defective proteostasis of mutated alpha-galactosidase A resulting in chronic endoplasmic reticulum stress and unfolded protein response of alpha-galactosidase A expressing cells as a contributor to Fabry disease pathogenesis.