Živná Martina, Lenders Malte, Kmoch Stanislav
Research Unit for Rare Diseases, Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czechia.
Section on Nephrology, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, North Carolina, USA.
Nephron. 2025 Mar 20:1-11. doi: 10.1159/000545388.
Clinical findings in Fabry disease have classically been attributed to loss-of-function variants in the GLA gene that result in α-galactosidase A deficiency, intracellular accumulation of globotriaosylceramides and clinical manifestations. However, over time, increasing number of patients have been identified with GLA variants causing either non-classic Fabry disease or having unclear clinical effects.
Searching for additional etiologic and lysosomal storage-independent factors, investigators have recently identified that certain missense GLA variants not only affect enzymatic activity, but also encode for misfolded α-galactosidase A that itself induces chronic endoplasmic reticulum stress and the unfolded protein response. Thus, Fabry disease pathogenesis may be caused by decreased enzymatic activity as well as cellular toxicity from accumulation of the misfolded α-galactosidase A protein, with the contribution of each factor determined by the type of the genetic variant and host factors.
Defective proteostasis and misfolding of certain missense α-galactosidase A variants induce chronic endoplasmic reticulum stress and the unfolded protein response that may contribute to intra-familial and inter-familial variation in disease penetrance and clinical expressivity. Pharmacologic modulation of defective proteostasis may have therapeutic implications in Fabry disease.
法布里病的临床症状传统上归因于GLA基因的功能丧失变异，该变异导致α-半乳糖苷酶A缺乏、球三糖神经酰胺在细胞内蓄积以及临床表现。然而，随着时间的推移，越来越多携带GLA变异的患者被发现，这些变异导致非典型法布里病或具有不明确的临床影响。
为了寻找其他病因和与溶酶体贮积无关的因素，研究人员最近发现某些错义GLA变异不仅影响酶活性，还编码错误折叠的α-半乳糖苷酶A，而这种酶本身会诱导慢性内质网应激和未折叠蛋白反应。因此，法布里病的发病机制可能是由酶活性降低以及错误折叠的α-半乳糖苷酶A蛋白蓄积导致的细胞毒性引起的，每个因素的作用程度由基因变异类型和宿主因素决定。
某些错义α-半乳糖苷酶A变异的蛋白质稳态缺陷和错误折叠会诱导慢性内质网应激和未折叠蛋白反应，这可能导致疾病外显率和临床表现在家族内和家族间存在差异。对缺陷蛋白质稳态的药物调节可能对法布里病具有治疗意义。
