Giroud-Gerbetant Judith, Sotillo Fernando, Hernández Gonzalo, Ruano Irene, Sebastián David, Fort Joana, Sánchez Mayka, Weiss Günter, Prats Neus, Zorzano Antonio, Palacín Manuel, Bodoy Susanna
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, U-731, Spain.
Mol Med. 2025 Jan 29;31(1):29. doi: 10.1186/s10020-025-01100-0.
Lysinuric protein intolerance is a rare autosomal disorder caused by mutations in the Slc7a7 gene that lead to impaired transport of neutral and basic amino acids. 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-whether intrinsic to hematopoietic cells or driven by external factors-remains 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.
We employed total inducible and cell type-specific Slc7a7 knockout mouse models to determine whether the hematological abnormalities observed in LPI are due to the loss of Slc7a7 function in hematopoietic cells. We analyzed erythropoiesis in these mice and performed bone marrow transplantation experiments to assess the role of Slc7a7 in erythroblasts and myeloid cells. The statistical significance of differences between groups was evaluated via standard statistical tests, including Student's t test and ANOVA.
Whole-body Slc7a7 knockout mice presented impaired erythropoiesis. However, this defect was not replicated in mice with Slc7a7 deficiency restricted to erythroblasts or myeloid cells, suggesting that the observed hematopoietic abnormalities are not due to intrinsic Slc7a7 loss in these cell types. Additionally, bone marrow transplants from control mice did not rescue the hematopoietic defects in Slc7a7-deficient mice, nor did the transplantation of Slc7a7-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.
The hematopoietic defects in the Lysinuric protein intolerance mouse model are not caused by intrinsic Slc7a7 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.
赖氨酸尿性蛋白不耐受症是一种罕见的常染色体疾病，由Slc7a7基因突变引起，该突变导致中性和碱性氨基酸转运受损。赖氨酸尿性蛋白不耐受症的金标准治疗方法包括低蛋白饮食和补充瓜氨酸。虽然这种方法部分改善了阳离子氨基酸血浆水平并缓解了一些症状，但长期治疗被认为是有害的，可能导致危及生命的并发症，其特征为广泛的血液学和免疫学异常。这些造血缺陷的具体原因——是造血细胞固有的还是由外部因素驱动的——仍不清楚。鉴于目前基于瓜氨酸治疗的局限性以及SLC7A7在红细胞生成中的未知作用，迫切需要研究受SLC7A7缺乏影响的途径。
我们采用了完全诱导型和细胞类型特异性的Slc7a7基因敲除小鼠模型，以确定在赖氨酸尿性蛋白不耐受症中观察到的血液学异常是否是由于造血细胞中Slc7a7功能丧失所致。我们分析了这些小鼠的红细胞生成，并进行了骨髓移植实验，以评估Slc7a7在成红细胞和髓细胞中的作用。通过标准统计检验，包括学生t检验和方差分析，评估组间差异的统计学意义。
全身Slc7a7基因敲除小鼠出现红细胞生成受损。然而，这种缺陷在Slc7a7缺乏仅限于成红细胞或髓细胞的小鼠中并未重现，这表明观察到的造血异常并非由于这些细胞类型中固有Slc7a7的缺失。此外，来自对照小鼠的骨髓移植未能挽救Slc7a7缺陷小鼠的造血缺陷，Slc7a7缺陷细胞的移植也未在对照受体中诱发缺陷。进一步研究表明，有缺陷的红细胞生成与肾脏中促红细胞生成素生成受损及随后的铁过载有关。
赖氨酸尿性蛋白不耐受症小鼠模型中的造血缺陷不是由造血细胞中固有Slc7a7的缺失引起的，而是由肾脏中促红细胞生成素生成受损引起的。这一发现为针对促红细胞生成素生成的治疗策略开辟了潜在途径，以解决赖氨酸尿性蛋白不耐受症患者的血液学异常。
