Gene expression analysis in GLA-mutant zebrafish revealed enhanced Ca2+ signaling similar to Fabry disease. fabry_disease_zebrafish_GLA

Fabry disease is an X-linked inborn metabolic disorder due to partial or complete deficiency of lysosomal α-galactosidase A activity. The disease is characterized by progressive renal insufficiency, with cardio and cerebrovascular involvement. The lack of experimental models of Fabry disease has limited the understanding of the disease and consequently has delayed the development of new therapies. Due to partial or complete deficiency of the lysosomal α-galactosidase A activity, the accumulation of glycosphingolipids is used as a marker. However, recent studies suggested that they are not an ideal marker for treatment monitoring or treatment response. Here we use our GLA-knockout zebrafish to investigate the possible biomarkers in an A4GALT-free-condition. We describe here an RNA sequencing analysis aiming to determine underlying transcriptomics signatures that could discriminate GLA-mutant fish from the wild-type fish in Gb3-free conditions. As in the FD, we found an upregulated Ca2+ signaling pathway accompanied by downregulated cardiac muscle contraction pathway. In addition, disrupted mitochondrial and lysosome-related pathways in the mutant were observed and tested using immunohistochemistry. Our results point out that our model can mimic the effects of GLA mutations independently of the Gb-3 accumulation and potentially can be used to find new targets that improve FD outcomes.