1. Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects
- Author
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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, 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], and Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF]
- Subjects
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 - Abstract
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.
- Published
- 2017
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