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

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  • 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
    Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, 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
    Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center)

  • Monique van Scherpenzeel

    (Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
    Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, 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
    Nijmegen Centre for Mitochondrial Disorders (NCMD), 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
    University Medical School of Leuven
    Radboudumc)

  • 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
    Maastricht University Medical Centre)

  • Tom H. Stevens

    (Institute of Molecular Biology, University of Oregon)

  • Dirk J. Lefeber

    (Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center
    Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center)

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.

Suggested Citation

  • 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 Steenber, 2016. "ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11600
    DOI: 10.1038/ncomms11600
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