AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Abstract Background Classic Fabry disease (FD) is caused by GLA mutations that result in enzymatic deficiency of alpha-galactosidase A (AGAL), lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic later-onset FD, patients have some preserved AGAL activity and a milder disease course, though female carriers may also be affected. While FD pathogenesis has been mostly attributed to catalytic deficiency of mutated AGAL, lysosomal storage and impairment of lysosomal functions, other pathogenic factors may be important, especially in non-classic later-onset FD. Methods We characterized the clinical, biochemical, genetic, molecular, cellular and organ pathology correlates of the p.L394P AGAL variant that was identified in six individuals with end-stage kidney disease by the Czech national screening program for FD and by further screening of 25 family members. Results Clinical findings revealed a milder clinical course with ~15% residual AGAL activity. Laboratory investigations documented intracellular retention of mutated AGAL with resulting ER stress and the unfolded protein response (UPR). Kidney biopsies did not show lysosomal storage. We observed similar findings of ER stress and UPR with several other classic and non-classic FD missense GLA variants. Conclusions We identified defective proteostasis of mutated AGAL resulting in chronic ER stress and UPR of AGAL expressing cells (hereafter referred to as AGALopathy) as an important contributor to FD pathogenesis. These findings provide insight into non-classic later-onset FD and may better explain clinical manifestations with implications for pathogenesis, clinical characterization and treatment of all FD forms. ### Competing Interest Statement G.D. received speakers honoraria and consultation fees from Sanofi, Takeda, Amicus, Chiesi; P.R. has been a consultant for Takeda Pharmaceuticals (formely Shire HGT). She has received speaker fees from Takeda Pharmaceuticals and Sanofi-Genzyme, travel and accomodation support from Takeda Pharmaceuticals and symposium reimbursement from Takeda Pharmaceuticals and Amicus Therapeutics. A.L. received speakers honoraria and research support from Sanofi, speakers honoraria and consultation fees from Takeda, Amicus, Chiesi, Avrobio and 4DMT. All remaining authors have nothing to disclose.