Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
Por:
Bodoy S, Sotillo F, Espino-Guarch M, Sperandeo MP, Ormazabal-Herrero A, Zorzano A, Sebastio G, Artuch-Iriberri R and Palacín M
Publicada:
1 nov 2019
Ahead of Print:
24 oct 2019
Resumen:
Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y(+)LAT1 transporter. LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible Slc7a7 knockout mouse (Slc7a7(-/-)). The Slc7a7(-/-) model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the Slc7a7(-/-) mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the Slc7a7(-/-) model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.
Filiaciones:
Bodoy S:
Institute for Research in Biomedicine (IRB Barcelona), the Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
Department of Biosciences, University of Vic, 08500 Vic, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08003 Barcelona, Spain.
Espino-Guarch M:
Sidra Medicine, Translational Medicine Department, Doha 26999, Qatar.
Sperandeo MP:
Department of Translational Medicine, Section of Pediatrics, Federico II University of Naples, 80138 Naples, Italy.
Ormazabal-Herrero A:
Department of Clinical Biochemistry, Hospital Sant Joan de Déu (HSJD), Esplugues del Llobregat, 08950 Barcelona, Spain.
Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950, Spain.
Zorzano A:
Centro de Investigación Biomédica en Obesidad (CIBEROB), Madrid, 28029, Spain.
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain.
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