title: ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation.
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.
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience and Radboud Institute for Molecular Life Sciences, Faculty of Science, Radboud University, 6525 GA Nijmegen, The Netherlands.
authors.forename: Eric J R
authors.initials: EJ
authors.lastname: Jansen
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.|Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Sharita
authors.initials: S
authors.lastname: Timal
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA.
authors.forename: Margret
authors.initials: M
authors.lastname: Ryan
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.|Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Angel
authors.initials: A
authors.lastname: Ashikov
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.|Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: van Scherpenzeel
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA.
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Graham
authors.affiliation: Metabolic Unit, Rambam Health Care Center, Rappaport School of Medicine, Technion, 3109601 Haifa, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: The Milman-David Biomedical Research Unit, 24 Hazevi Avenue, 34355 Haifa, Israel.
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Iancu
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Kimiyo
authors.initials: K
authors.lastname: Raymond
authors.affiliation: Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Gerry
authors.initials: G
authors.lastname: Steenbergen
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Christian
authors.identifier: 0000-0003-1693-9699
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Huijben
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience and Radboud Institute for Molecular Life Sciences, Faculty of Science, Radboud University, 6525 GA Nijmegen, The Netherlands.
authors.forename: Nick H M
authors.initials: NH
authors.lastname: van Bakel
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Maeda
authors.affiliation: Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.|Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders (NCMD), Radboud university medical center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Protein Laboratory, Children's Memorial Health Institute, 04730 Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Adamowicz
authors.affiliation: Temple Street Children's University Hospital, Temple Street, Dublin 1, DC01 YC67, Ireland.
authors.forename: Ellen
authors.initials: E
authors.lastname: Crushell
authors.affiliation: Department of Laboratory Medicine, Medical Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Koenen
authors.affiliation: Personalized Genomic Medicine Pediatric Genetics and Metabolism Goryeb Children's Hospital, Morristown, New Jersey 07960, USA.
authors.forename: Darius
authors.initials: D
authors.lastname: Adams
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Vodopiutz
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Greber-Platzer
authors.affiliation: Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: HELIOS Kliniken Krefeld, Children's Hospital, Lutherplatz 40, 47805 Krefeld, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dueckers
authors.affiliation: Department of Pediatrics, Tulane University Medical School, New Orleans, Los Angeles 70112, USA.|Department of Pediatrics, University Medical School of Leuven, 3000 Leuven, Belgium.|Department of Pediatrics, Radboudumc, 6525GA, Nijmegen, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.affiliation: Screening Department, Institute of Mother and Child, 01-211 Warsaw, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Sykut-Cegielska
authors.affiliation: Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience and Radboud Institute for Molecular Life Sciences, Faculty of Science, Radboud University, 6525 GA Nijmegen, The Netherlands.
authors.forename: Gerard J M
authors.initials: GJ
authors.lastname: Martens
authors.affiliation: Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: HELIOS Kliniken Krefeld, Children's Hospital, Lutherplatz 40, 47805 Krefeld, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Niehues
authors.affiliation: Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands.
authors.forename: Martijn A
authors.initials: MA
authors.lastname: Huynen
authors.affiliation: Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.|Department of Clinical Genetics, Maastricht University Medical Centre, 6229HX Maastricht, The Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Stevens
authors.affiliation: Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.|Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D006031:Glycosylation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D017386:Sequence Homology, Amino Acid; D025262:Vacuolar Proton-Translocating ATPases / Q000172:deficiency / Q000235:genetics*; D055815:Young Adult
chemical_list: C089598:ATP6AP1 protein, human; D025262:Vacuolar Proton-Translocating ATPases