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

• DOI: 10.1084/jem.20170453
• Publication Date: 2017-12-18T20:55:24Z
• Authors: 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
• Keywords: Male; Vacuolar Proton-Translocating ATPases; Glycosylation; 572; Adolescent; Endoplasmic Reticulum-Associated Degradation;Brain;Humans;Liver;Cutis Laxa;Male;Lipids;Infant;Receptors, Cell Surface;Autophagy;Young Adult;Genes, X-Linked;Base Sequence;Fibroblasts;Vacuolar Proton-Translocating ATPases;Amino Acid Sequence;Drosophila Proteins;Glycosylation;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; Immunology; Medical and Health Sciences; Cutis Laxa; Young Adult; Mice; Rare Diseases; Neural Stem Cells; Genes, X-Linked; Receptors; Autophagy; 2.1 Biological and endogenous factors; Animals; Drosophila Proteins; Humans; Amino Acid Sequence; Aetiology; Membrane Protein; Protein Processing; Research Articles; Base Sequence; Liver Disease; Liver Diseases; Post-Translational; Membrane Proteins; Brain; Infant; Blood Proteins; Endoplasmic Reticulum-Associated Degradation; X-Linked; Fibroblasts; Lipids; [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry; Proton-Translocating ATPases; Drosophila melanogaster; Genes; Liver; Cell Surface; Mutation; Psychomotor Disorders; Digestive Diseases; Protein Binding

The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in endoplasmic reticulum with assembly proton pore V0, which controlled by a group factors. Here, we identify two hemizygous missense mutations extracellular domain accessory V-ATPase subunit ATP6AP2 (also known as [pro]renin receptor) responsible for glycosylation disorder liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that deficiency mouse caused hypoglycosylation serum proteins autophagy defects. introduction one into Drosophila led to reduced survival altered lipid metabolism. further demonstrate liver-like fat body, autophagic dysregulation was associated defects lysosomal acidification mammalian target rapamycin (mTOR) signaling. Finally, both impaired protein stability interaction ATP6AP1, member V0 complex. Collectively, our data suggest lead subsequent autophagy.