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The gold standard treatment for lysinuric protein intolerance involves a low-protein diet and citrulline supplementation. While this approach partially improves cationic amino acid plasma levels and alleviates some symptoms, long-term treatment is suggested to be detrimental and may lead to life-threatening complications characterized by a wide range of hematological and immunological abnormalities. The specific cause of these hematopoietic defects\u2014whether intrinsic to hematopoietic cells or driven by external factors\u2014remains unclear. Given the limitations of current citrulline-based treatments and the unknown role of SLC7A7 in red blood cell production, there is an urgent need to investigate the pathways affected by SLC7A7 deficiency.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>We employed total inducible and cell type-specific <jats:italic>Slc7a7<\/jats:italic> knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of <jats:italic>Slc7a7<\/jats:italic> function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of <jats:italic>Slc7a7<\/jats:italic> in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student\u2019s <jats:italic>t<\/jats:italic> test and ANOVA.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Whole-body <jats:italic>Slc7a7<\/jats:italic> knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with <jats:italic>Slc7a7<\/jats:italic> deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic <jats:italic>Slc7a7<\/jats:italic> loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in <jats:italic>Slc7a7<\/jats:italic>-deficient mice, nor did the transplantation of <jats:italic>Slc7a7<\/jats:italic>-deficient cells induce defects in control recipients. Further investigation indicated that defective erythropoiesis is linked to impaired erythropoietin production in the kidney and subsequent iron overload.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic <jats:italic>Slc7a7<\/jats:italic> loss in hematopoietic cells but rather by impaired erythropoietin production in the kidney. This finding opens potential avenues for therapeutic strategies targeting erythropoietin production to address hematological abnormalities in humans with lysinuric protein intolerance.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s10020-025-01100-0","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T05:39:46Z","timestamp":1738129186000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Defective Slc7a7 transport reduces erythropoietin compromising erythropoiesis"],"prefix":"10.1186","volume":"31","author":[{"given":"Judith","family":"Giroud-Gerbetant","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Sotillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gonzalo","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Ruano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Sebasti\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joana","family":"Fort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayka","family":"S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00fcnter","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neus","family":"Prats","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Zorzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Palac\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Bodoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"1100_CR1","doi-asserted-by":"publisher","first-page":"81","DOI":"10.3233\/TRD-190035","volume":"5","author":"F Alqarajeh","year":"2020","unstructured":"Alqarajeh F, Omorodion J, Bosfield K, et al. 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