Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects
| Autor: | Maria Clara Guida, Dulce Quelhas, Stefanie Jäger, Ganna Panasyuk, Thorsten Marquardt, Sandrine Duvet, Erika Souche, Oliver Kretz, Virginie Hauser, Gert Matthijs, Magda Cannata Serio, Maria A. Rujano, Esther M. Maier, Thomas D. Bird, Julien H. Park, Michael Schwake, Wendy H. Raskind, Janine Reunert, Peter Freisinger, Romain Péanne, François Foulquier, Daisy Rymen, Paula Garcia, Matias Simons, Nevan J. Krogan, Yoshinao Wada, Susana Nobre |
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| Přispěvatelé: | Université Paris Descartes - Paris 5 (UPD5), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Center for Human Genetics, University of Leuven School of Medicine, SCHOOL of MEDICINE [Louvain], Université Catholique de Louvain = Catholic University of Louvain (UCL)-Université Catholique de Louvain = Catholic University of Louvain (UCL), University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Reutlingen University, University of California [San Francisco] (UCSF), University of California, Centre for Biological Signaling Studies [Freiburg] (BIOSS), University of Freiburg [Freiburg], Hospitais da Universidade de Coimbra (H.U.C.), University of Coimbra [Portugal] (UC), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto, University of Washington [Seattle], Universität Bielefeld = Bielefeld University, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-ACHN-0013,NEPHROFLY,Utilisation de Drosophila melanogaster pour étudier les maladies génétiques du rein(2014), ANR-16-CE14-0029,NUTRISENSPIK,Déterminants moléculaires de l'homéostasie hépatique nutritive(2016), European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California [San Francisco] (UC San Francisco), University of California (UC), Universidade do Porto = University of Porto, Université de Lille-Centre National de la Recherche Scientifique (CNRS), CNRS, Université de Lille, Université Paris Descartes - Paris 5 [UPD5], Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)], University Hospital Münster - Universitaetsklinikum Muenster [Germany] [UKM], University of California [San Francisco] [UC San Francisco], Centre for Biological Signaling Studies [Freiburg] [BIOSS], Hospitais da Universidade de Coimbra [H.U.C.], Faculdade de Medicina da Universidade do Porto [FMUP], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF] |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Glycosylation Endoplasmic Reticulum-Associated Degradation Brain Humans Liver Cutis Laxa Lipids Infant Receptors Cell Surface Autophagy Young Adult Genes X-Linked Base Sequence Fibroblasts Vacuolar Proton-Translocating ATPases Amino Acid Sequence Drosophila Proteins Neural Stem Cells Animals Blood Proteins Proton-Translocating ATPases Adolescent Protein Binding Mice Membrane Protein Protein Processing Post-Translational Mutation Liver Diseases Drosophila melanogaster Psychomotor Disorders medicine.disease_cause Medical and Health Sciences chemistry.chemical_compound Receptors Immunology and Allergy Missense mutation Research Articles 3. Good health Cell biology [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry Cell Surface Psychomotor disorder Immunology Endoplasmic-reticulum-associated protein degradation Article 03 medical and health sciences medicine Protein Processing ATP6AP2 Endoplasmic reticulum Post-Translational Membrane Proteins X-Linked 030104 developmental biology chemistry Genes |
| Zdroj: | The Journal of experimental medicine, vol 214, iss 12 The Journal of Experimental Medicine The Journal of Experimental Medicine, 2017, The Journal of Experimental Medicine, 214 (12), pp.3707-3729. ⟨10.1084/jem.20170453⟩ Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação instacron:RCAAP |
| ISSN: | 1540-9538 |
| Popis: | Rujano et al. report mutations in ATP6AP2 leading to liver disease, immunodeficiency, and psychomotor impairment. ATP6AP2 deficiency impairs the assembly and function of the V-ATPase proton pump, causing defects in protein glycosylation and autophagy. The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V-ATPase subunit ATP6AP2 (also known as the [pro]renin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into Drosophila led to reduced survival and altered lipid metabolism. We further demonstrate that in the liver-like fat body, the autophagic dysregulation was associated with defects in lysosomal acidification and mammalian target of rapamycin (mTOR) signaling. Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex. Collectively, our data suggest that the missense mutations in ATP6AP2 lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy. |
| Databáze: | OpenAIRE |
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