Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects

Maria A Rujano; Magda Cannata Serio; Ganna Panasyuk; Romain Péanne; Janine Reunert; Daisy Rymen; Virginie Hauser; Julien H Park; Peter Freisinger; Erika Souche; Maria Clara Guida; Esther M Maier; Yoshinao Wada; Stefanie Jäger; Nevan J Krogan; Oliver Kretz; Susana Nobre; Paula Garcia; Dulce Quelhas; Thomas D Bird; Wendy H Raskind; Michael Schwake; Sandrine Duvet; Francois Foulquier; Gert Matthijs; Thorsten Marquardt; Matias Simons

doi:10.1084/jem.20170453

Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects

J Exp Med. 2017 Dec 4;214(12):3707-3729. doi: 10.1084/jem.20170453. Epub 2017 Nov 10.

Authors

Maria A Rujano^{1

2}, Magda Cannata Serio^{1

2}, Ganna Panasyuk^{3

4}, Romain Péanne⁵, Janine Reunert⁶, Daisy Rymen⁵, Virginie Hauser^{1

4}, Julien H Park⁶, Peter Freisinger⁷, Erika Souche⁵, Maria Clara Guida^{1

4}, Esther M Maier⁸, Yoshinao Wada⁹, Stefanie Jäger¹⁰, Nevan J Krogan¹⁰, Oliver Kretz¹¹, Susana Nobre¹², Paula Garcia¹², Dulce Quelhas¹³, Thomas D Bird^{14

15}, Wendy H Raskind¹⁶, Michael Schwake¹⁷, Sandrine Duvet¹⁸, Francois Foulquier¹⁸, Gert Matthijs⁵, Thorsten Marquardt⁶, Matias Simons^{19

2}

Affiliations

¹ Laboratory of Epithelial Biology and Disease, Imagine Institute, Paris, France.
² Université Paris Descartes-Sorbonne Paris Cité, Imagine Institute, Paris, France.
³ Institut Necker-Enfants Malades, Paris, France.
⁴ Institut National de la Santé et de la Recherche Medicale U1151/Centre National de la Recherche Scientifique UMR 8253, Paris, France.
⁵ University of Leuven (KU Leuven), Center for Human Genetics, Leuven, Belgium.
⁶ Universitätsklinikum Münster, Klinik für Kinder- und Jugendmedizin, Münster, Germany.
⁷ Kreiskliniken Reutlingen, Klinik für Kinder- und Jugendmedizin, Klinikum am Steinenberg, Reutlingen, Germany.
⁸ Dr. von Haunersches Kinderspital der Universität München, München, Germany.
⁹ Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
¹⁰ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA.
¹¹ Centre for Biological Signaling Studies BIOSS, University of Freiburg, Freiburg, Germany.
¹² Metabolic Reference Center, Coimbra University Hospital Center, Coimbra, Portugal.
¹³ Biochemical Genetics Unit, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal.
¹⁴ Department of Neurology, University of Washington, Seattle, WA.
¹⁵ Geriatric Research Center, Veterans Administration Medical Center, Seattle, WA.
¹⁶ Department of Medicine, University of Washington, Seattle, WA.
¹⁷ Faculty of Chemistry/Biochemistry III, University Bielefeld, Bielefeld, Germany.
¹⁸ Université Lille, Centre National de la Recherche Scientifique UMR 8576, Unité de Glycobiologie Structurale et Fonctionnelle, Lille, France.
¹⁹ Laboratory of Epithelial Biology and Disease, Imagine Institute, Paris, France matias.simons@institutimagine.org.

Abstract

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.

MeSH terms

Adolescent
Amino Acid Sequence
Animals
Autophagy*
Base Sequence
Blood Proteins / metabolism
Brain / embryology
Brain / pathology
Cutis Laxa / complications
Cutis Laxa / pathology
Drosophila Proteins / genetics*
Drosophila Proteins / metabolism
Drosophila melanogaster / metabolism
Endoplasmic Reticulum-Associated Degradation
Fibroblasts / pathology
Genes, X-Linked*
Glycosylation
Humans
Infant
Lipids / chemistry
Liver / pathology
Liver Diseases / complications
Liver Diseases / pathology
Male
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Mutation / genetics*
Neural Stem Cells / cytology
Neural Stem Cells / metabolism
Protein Binding
Protein Processing, Post-Translational
Proton-Translocating ATPases / deficiency
Proton-Translocating ATPases / genetics*
Proton-Translocating ATPases / metabolism
Psychomotor Disorders / complications
Psychomotor Disorders / pathology
Receptors, Cell Surface / chemistry
Receptors, Cell Surface / deficiency
Receptors, Cell Surface / genetics*
Receptors, Cell Surface / metabolism
Vacuolar Proton-Translocating ATPases / chemistry
Vacuolar Proton-Translocating ATPases / deficiency
Vacuolar Proton-Translocating ATPases / genetics*
Young Adult

Substances

ATP6AP2 protein, Drosophila
ATP6AP2 protein, human
ATP6AP2 protein, mouse
Blood Proteins
Drosophila Proteins
Lipids
Membrane Proteins
Receptors, Cell Surface
Vacuolar Proton-Translocating ATPases
Proton-Translocating ATPases

Associated data

RefSeq/NM_005765

Grants and funding

R01 NS069719/NS/NINDS NIH HHS/United States