SLC7A7 DEFICIENCY CAUSES RENAL DYSFUNCTION AND REDUCED ERYTHROPOIETIN COMPROMISING ERYTHROPOIESIS

Lysinuric Protein Intolerance (LPI) is an inborn metabolic disorder caused by mutations in SLC7A7, a cationic amino acid transporter leading to reduced plasma levels of cationic amino acids and urea cycle abnormalities. Clinical manifestations in patients are diverse, often involving severe hematological, immunological anomalies, and kidney failure. Our investigation demonstrates that Slc7a7 deficiency in mice causes iron overload, erythropoiesis dysfunction, and diminished erythrocyte size. We ruled out a direct intrinsic impact of Slc7a7 on erythroid or myeloid lineages using cell-lineage-specific mouse models, focusing on the systemic environment as the main player in the mice's phenotype. Regarding iron metabolism, we suggest that reduced plasma erythropoietin triggers a significant iron overload, as erythropoietin administration restores normal iron levels and mitigates hematological alterations. Notably, we observed kidney failure in LPI mice, mirroring the clinical scenario in LPI patients. Recovery experiments with citrulline treatment were able to restore kidney cortical mitochondrial respiration, prevent renal fibrosis, and recover EPO levels. Interestingly, human LPI is associated with hyperferritinemia but not iron overload, a trait that might be obscured by citrulline treatment. This study unveils a previously unrecognized role of EPO in the disease and suggests EPO as a promising therapeutic strategy for LPI patients.