ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation

Eric J. R. Jansen, Sharita Timal, Margret Ryan, Angel Ashikov, Monique van Scherpenzeel, Laurie A. Graham, Hanna Mandel, Alexander Hoischen, Theodore C. Iancu, Kimiyo Raymond, Gerry Steenbergen, Christian Gilissen, Karin Huijben, Nick H. M. van Bakel, Yusuke Maeda, Richard J. Rodenburg, Maciej Adamowicz, Ellen Crushell, Hans Koenen, Darius Adams, Julia Vodopiutz, Susanne Greber-Platzer, Thomas Müller, Gregor Dueckers, Eva Morava, Jolanta Sykut-Cegielska, Gerard J. M. Martens, Ron A. Wevers, Tim Niehues, Martijn A. Huynen, Joris A. Veltman, Tom H. Stevens () and Dirk J. Lefeber ()
Additional contact information
Eric J. R. Jansen: Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience and Radboud Institute for Molecular Life Sciences, Faculty of Science, Radboud University
Sharita Timal: Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
Margret Ryan: Institute of Molecular Biology, University of Oregon
Angel Ashikov: Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
Monique van Scherpenzeel: Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
Laurie A. Graham: Institute of Molecular Biology, University of Oregon
Hanna Mandel: Metabolic Unit, Rambam Health Care Center, Rappaport School of Medicine, Technion
Alexander Hoischen: Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center
Theodore C. Iancu: The Milman-David Biomedical Research Unit
Kimiyo Raymond: Mayo College of Medicine
Gerry Steenbergen: Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Christian Gilissen: Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center
Karin Huijben: Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Nick H. M. van Bakel: Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience and Radboud Institute for Molecular Life Sciences, Faculty of Science, Radboud University
Yusuke Maeda: Research Institute for Microbial Diseases, Osaka University
Richard J. Rodenburg: Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Maciej Adamowicz: Protein Laboratory, Children’s Memorial Health Institute
Ellen Crushell: Temple Street Children’s University Hospital
Hans Koenen: Medical Immunology, Radboud University Medical Center
Darius Adams: Personalized Genomic Medicine Pediatric Genetics and Metabolism Goryeb Children’s Hospital
Julia Vodopiutz: Medical University of Vienna
Susanne Greber-Platzer: Medical University of Vienna
Thomas Müller: Medical University of Innsbruck
Gregor Dueckers: HELIOS Kliniken Krefeld, Children’s Hospital, Lutherplatz 40
Eva Morava: Tulane University Medical School
Jolanta Sykut-Cegielska: Institute of Mother and Child
Gerard J. M. Martens: Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience and Radboud Institute for Molecular Life Sciences, Faculty of Science, Radboud University
Ron A. Wevers: Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Tim Niehues: HELIOS Kliniken Krefeld, Children’s Hospital, Lutherplatz 40
Martijn A. Huynen: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center
Joris A. Veltman: Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center
Tom H. Stevens: Institute of Molecular Biology, University of Oregon
Dirk J. Lefeber: Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract The V-ATPase is the main regulator of intra-organellar acidification. Assembly of this complex has extensively been studied in yeast, while limited knowledge exists for man. We identified 11 male patients with hemizygous missense mutations in ATP6AP1, encoding accessory protein Ac45 of the V-ATPase. Homology detection at the level of sequence profiles indicated Ac45 as the long-sought human homologue of yeast V-ATPase assembly factor Voa1. Processed wild-type Ac45, but not its disease mutants, restored V-ATPase-dependent growth in Voa1 mutant yeast. Patients display an immunodeficiency phenotype associated with hypogammaglobulinemia, hepatopathy and a spectrum of neurocognitive abnormalities. Ac45 in human brain is present as the common, processed ∼40-kDa form, while liver shows a 62-kDa intact protein, and B-cells a 50-kDa isoform. Our work unmasks Ac45 as the functional ortholog of yeast V-ATPase assembly factor Voa1 and reveals a novel link of tissue-specific V-ATPase assembly with immunoglobulin production and cognitive function.

Date: 2016
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DOI: 10.1038/ncomms11600

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