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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/204981
Unraveling potential disease modifiers of myotonic dystrophy type 1
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[eng] Lysinuric Protein Intolerance (LPI) is a rare autosomal recessive disorder caused by mutations in the SLC7A7 gene, which encodes the y+LAT1 transporter. LPI presents a pleiotropic phenotype that varies among patients, with common features including immunological and hematological disorders such as microcytic anemia, pulmonary alveolar proteinosis, and hemophagocytic lymphohistiocytosis. Furthermore, advanced stages of the disease often lead to chronic kidney disease and end-stage renal failure. The mechanism behind the development of the hematological and immunological abnormalities in patients with LPI remains elusive due to the impossibility of analyzing these clinical aspects in human patients with LPI.
In the first chapter of this thesis, we utilized a global Slc7a7 knockout mouse model to investigate the hematological aspects of LPI. We observed reduced mean corpuscular volume in circulating erythrocytes, though not reaching clinical anemia levels. Prolonged periods of low protein diet exacerbated this phenotype, resulting in diminished hematocrit and mean corpuscular hemoglobin. To investigate a plausible mechanism for the changes observed in red blood cells we investigated the process of red blood cell generation, and observed that Slc7a7 knockout mice showed diminished erythropoiesis, a trait not rescued by bone marrow transplantation. Intriguingly, iron overload was evident in these mice, potentially due to reduced iron utilization during erythropoiesis. Notably, we established that erythropoietin is the main cause of diminished red blood cell production as exogenous erythropoietin administration not only restores normal erythropoiesis but also iron homeostasis. Finally, we discovered that renal erythropoietin-producing cells express Slc7a7, though its expression was dispensable for erythropoietin production.
In the second chapter, we tackled how Slc7a7 expression affects mature cell development. To do so, we first phenotypically analyzed mature cell population within the bone marrow and observed that Slc7a7 knockout mice show increased T cell numbers and decreased B cell numbers. Single-cell profiling unveiled the expression of Slc7a7 in a subset of B cells and neutrophils, with the absence of the transporter leading to significant transcriptional changes in the latter. Subsequently, bone marrow transplant experiments shed light in the interplay between the extrinsic and the intrinsic factor derived of Slc7a7 absence. While the T cell phenotype appeared to result
solely from metabolic alterations, the neutrophil phenotype appeared to arise from both
Slc7a7 absence and changes in the bone marrow microenvironment.
Collectively, our findings offer potential mechanisms underlying the immunological and hematological alterations seen in human LPI patients. Furthermore, we demonstrate that Slc7a7 absence in neutrophils exacerbates inflammatory responses, shedding light on the complex pathophysiology of LPI.
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GIROUD-GERNETANT DEUS, Judith. Unraveling potential disease modifiers of myotonic dystrophy type 1. [consulta: 5 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/204981]