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Lookup NU author(s): Sarah Orr, Dr Elisa Molinari, Dr Katrina Wood, Dr Shalabh Srivastava, Dr Colin Miles, Dr Holly MabillardORCiD, Zac Sentell, Dr Marco TrevisanORCiD, Dr Juliana Arcila GalvisORCiD, Professor John SayerORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 The Author(s). Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to glycosphingolipid accumulation and progressive organ damage. Renal involvement is a major complication, yet diagnosis often requires an invasive kidney biopsy, and follow-up relies on indirect biomarkers or imaging, which lack specificity. Here, we present human urine-derived renal epithelial cells (hURECs) as a minimally invasive alternative for phenotyping renal Fabry disease and monitoring treatment response. Using hURECs from a newly diagnosed male Fabry disease patient, transmission electron microscopy (TEM) revealed lysosomal inclusions consistent with native kidney biopsy findings. Bulk RNA sequencing (RNA-seq) identified a transcriptomic disease signature, including dysregulated pathways involved in lipid metabolism homeostasis, ion transport, endoplasmic reticulum stress response, and collagen processing. Following systemic treatment of the patient with chaperone therapy, partial amelioration of the hUREC transcriptomic signature was observed during the first few months. However, by nine months, the signature began reverting toward baseline, correlating with continued kidney function decline. This prompted a transition to enzyme replacement therapy, with early evaluations showing transcriptomic stabilization. Our findings demonstrate that hURECs replicate key structural and molecular markers of renal Fabry disease and offer a non-invasive platform for longitudinal assessment of treatment response. TEM of hURECs provides a diagnostic alternative to biopsy, while RNA-seq-based transcriptomic profiling offers a sensitive and dynamic view of molecular changes, including key dysregulated pathways. This dual utility positions hURECs as a novel tool for improving the diagnosis, monitoring, and personalized management of kidney involvement in Fabry disease.
Author(s): Sudhindar PD, Orr SE, Miller-Hodges E, Molinari E, Wood K, Srivastava S, Miles CG, Mabillard HR, Sentell ZT, Trevisan-Herraz M, Arcila-Galvis JE, Sayer JA
Publication type: Article
Publication status: Published
Journal: Clinical Science
Year: 2025
Volume: 139
Issue: 14
Pages: 791-808
Online publication date: 28/07/2025
Acceptance date: 04/07/2025
Date deposited: 18/08/2025
ISSN (print): 0143-5221
ISSN (electronic): 1470-8736
Publisher: Portland Press
URL: https://doi.org/10.1042/CS20255570
DOI: 10.1042/CS20255570
Data Access Statement: The gene quantification data for all samples, including expression values for each gene across the genome, are publicly available and can be accessed at https://doi.org/10.6084/m9.figshare.28310816 Due to the presence of patient-sensitive genetic information, the raw sequencing data and alignment files cannot be made publicly available. However, these data are available upon reasonable request to the corresponding author. Supplementary tables, containing the full results of the differential expression analysis (Table S1) and enrichment analysis (Table S2), can be accessed as part of the supplementary materials. All in-house scripts used for data processing and analysis are available in the GitHub repository at https://github.com/juearcilaga/Fabry_hUREC_Transcriptomics/tree/main.
PubMed id: 40673439
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