Renal proteomic landscape of a patient with Fanconi renotubular syndrome carrying a novel GATM variant

Background Fanconi renotubular syndrome (FRTS) is a rare Mendelian disorder characterized by proximal tubular dysfunction. FRTS type 1 (FRTS1) has been associated with heterozygous variants in GATM , encoding mitochondrial glycine amidinotransferase. Although GATM -related mitochondrial abnormalities have been proposed to contribute to tubular injury, the molecular alterations in human kidney tissue remain incompletely understood. Methods Proteomic profiling was conducted on formalin-fixed paraffin-embedded renal biopsy tissue obtained from a patient with FRTS carrying a novel heterozygous missense variant in GATM (NM_001482.3; exon 6: c.949C>T, p.Leu317Phe). Protein abundance was quantified by data-independent acquisition mass spectrometry. Proteins showing marked deviations from control specimens were identified using a Z-score-based approach. Subsequent analyses included Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment, gene set enrichment analysis, gene set variation analysis, and protein-protein interaction network analysis. Results Beyond the identification of a novel GATM variant, this study provides an exploratory proteomic characterization of renal tissue alterations in a patient with FRTS. Proteomic profiling identified three major groups of altered molecular signatures involving proteasome-related proteins, coat protein complex II-mediated vesicular trafficking-associated proteins, and cytoskeleton- and adhesion-related proteins. Conclusions This study represents the first proteomic profiling of FRTS in its native tissue context. The identified proteomic alterations provide an exploratory framework for understanding renal tissue changes associated with FRTS and establish a resource for future validation studies.