KEY POINTS: The clinical significance of a number of missense variants of α-galactosidase A is often ambiguous. Defective proteostasis of some missense α-galactosidase A variants induced chronic endoplasmic reticulum stress and the unfolded protein response. Endoplasmic reticulum stress and the unfolded protein response may explain clinical manifestations of non-classic Fabry disease. BACKGROUND: Classic Fabry disease is caused by GLA mutations that result in loss of enzymatic activity of α-galactosidase A, lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic Fabry disease, patients have some preserved α-galactosidase A activity and a milder disease course. Heterozygous female patients may also be affected. While Fabry disease pathogenesis has been mostly attributed to catalytic deficiency of mutated α-galactosidase A, lysosomal storage, and impairment of lysosomal functions, other pathogenic factors may contribute, especially in nonclassic Fabry disease. METHODS: We characterized the genetic, clinical, biochemical, molecular, cellular, and organ pathology correlates of the p.L394P α-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 an additional 24 family members. RESULTS: Clinical findings in affected male patients revealed a milder clinical course, with approximately 15% residual α-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 α-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 α-galactosidase A variants. CONCLUSIONS: We identified defective proteostasis of mutated α-galactosidase A resulting in chronic endoplasmic reticulum stress and unfolded protein response of α-galactosidase A expressing cells as a contributor to Fabry disease pathogenesis.

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