In vitro characterization of cells derived from a patient with the GLA variant c.376A>G (p.S126G) highlights a non-pathogenic role in Fabry disease

• DOI: 10.1016/j.ymgmr.2023.101029
• Publication Date: 2023-11-25T17:11:21Z
• Authors: Maximilian Breyer; Julia Grüner; Alexandra Klein; Laura Finke; Katharina Klug; Markus Sauer; Nurcan Üçeyler
• Keywords: Globotriaosylceramide; Cell type

Fabry disease (FD) is a life-limiting disorder characterized by intracellular globotriaosylceramide (Gb3) accumulations. The underlying α-galactosidase A (α-GAL A) deficiency caused variants in the gene GLA. Variants of unknown significance (VUS) are frequently found GLA and challenge clinical management. Here, we investigated 49-year old man with cryptogenic lacunar cerebral stroke chance finding VUS S126G, who was sent to our center for diagnosis initiation costly life-long FD-specific treatment. We combined examination vitro investigations dermal fibroblasts (HDF), induced pluripotent stem cells (iPSC), iPSC-derived sensory neurons. analyzed α-GAL activity iPSC, Gb3 accumulation all three cell types, action potential firing Neurological small nerve fiber assessment normal except reduced distal skin innervation. S126G iPSC showed compared controls no deposits were types. Baseline electrophysiological characteristics neurons difference healthy as patch-clamp recordings. pioneer multi-level cellular characterization using types derived from patient provide further evidence benign nature GLA, which great importance management such cases practice.