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.

Maria A Rujano ¹ ², Magda Cannata Serio ¹ ², Ganna Panasyuk ³ ⁴, Romain Péanne ⁵, Janine Reunert ⁶, Daisy Rymen ⁵, Virginie Hauser ¹ ⁴, Julien H Park ⁶, Peter Freisinger ⁷, Erika Souche ⁵, Maria Clara Guida ¹ ⁴, Esther M Maier ⁸, Yoshinao Wada ⁹, Stefanie Jäger ¹⁰, Nevan J Krogan ¹⁰, Oliver Kretz ¹¹, Susana Nobre ¹², Paula Garcia ¹², Dulce Quelhas ¹³, Thomas D Bird ¹⁴ ¹⁵, Wendy H Raskind ¹⁶, Michael Schwake ¹⁷, Sandrine Duvet ¹⁸, Francois Foulquier ¹⁸, Gert Matthijs ⁵, Thorsten Marquardt ⁶, 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.

PMID: 29127204 DOI: 10.1084/jem.20170453

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.

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