Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease

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 n...

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Autores: Bodoy i Salvans, Susanna, Sotillo Rodríguez, Fernando, Espino-Guarch, Meritxell, Sperandeo, Maria Pia, Ormazabal Herrero, Aida, Zorzano Olarte, Antonio, Sebastio, Gianfranco, Artuch Iriberri, Rafael, Palacín Prieto, Manuel
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/183784
Acesso em linha:https://hdl.handle.net/2445/183784
Access Level:acceso abierto
Palavra-chave:Malalties rares
Amoníac
Sang
Rare diseases
Ammonia
Blood
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spelling Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance DiseaseBodoy i Salvans, SusannaSotillo Rodríguez, FernandoEspino-Guarch, MeritxellSperandeo, Maria PiaOrmazabal Herrero, AidaZorzano Olarte, AntonioSebastio, GianfrancoArtuch Iriberri, RafaelPalacín Prieto, ManuelMalalties raresAmoníacSangRare diseasesAmmoniaBloodLysinuric 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.MDPI2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/183784Articles publicats en revistes (Bioquímica i Biomedicina Molecular)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/ijms20215294International Journal of Molecular Sciences, 2019, vol. 20, num. 21, p. 1-15https://doi.org/10.3390/ijms20215294cc-by (c) Bodoy i Salvans, Susanna et al., 2019https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1837842026-05-27T06:46:51Z
dc.title.none.fl_str_mv Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
title Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
spellingShingle Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
Bodoy i Salvans, Susanna
Malalties rares
Amoníac
Sang
Rare diseases
Ammonia
Blood
title_short Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
title_full Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
title_fullStr Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
title_full_unstemmed Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
title_sort Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease
dc.creator.none.fl_str_mv Bodoy i Salvans, Susanna
Sotillo Rodríguez, Fernando
Espino-Guarch, Meritxell
Sperandeo, Maria Pia
Ormazabal Herrero, Aida
Zorzano Olarte, Antonio
Sebastio, Gianfranco
Artuch Iriberri, Rafael
Palacín Prieto, Manuel
author Bodoy i Salvans, Susanna
author_facet Bodoy i Salvans, Susanna
Sotillo Rodríguez, Fernando
Espino-Guarch, Meritxell
Sperandeo, Maria Pia
Ormazabal Herrero, Aida
Zorzano Olarte, Antonio
Sebastio, Gianfranco
Artuch Iriberri, Rafael
Palacín Prieto, Manuel
author_role author
author2 Sotillo Rodríguez, Fernando
Espino-Guarch, Meritxell
Sperandeo, Maria Pia
Ormazabal Herrero, Aida
Zorzano Olarte, Antonio
Sebastio, Gianfranco
Artuch Iriberri, Rafael
Palacín Prieto, Manuel
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Malalties rares
Amoníac
Sang
Rare diseases
Ammonia
Blood
topic Malalties rares
Amoníac
Sang
Rare diseases
Ammonia
Blood
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/183784
url https://hdl.handle.net/2445/183784
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/ijms20215294
International Journal of Molecular Sciences, 2019, vol. 20, num. 21, p. 1-15
https://doi.org/10.3390/ijms20215294
dc.rights.none.fl_str_mv cc-by (c) Bodoy i Salvans, Susanna et al., 2019
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Bodoy i Salvans, Susanna et al., 2019
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.300719

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