2. Academic Validation
  3. ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation

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

  • Nat Commun. 2016 May 27;7:11600. doi: 10.1038/ncomms11600.
Eric J R Jansen 1,  Sharita Timal 2 3,  Margret Ryan 4,  Angel Ashikov 2 3,  Monique van Scherpenzeel 2 3,  Laurie A Graham 4,  Hanna Mandel 5,  Alexander Hoischen 6,  Theodore C Iancu 7,  Kimiyo Raymond 8,  Gerry Steenbergen 3,  Christian Gilissen 6,  Karin Huijben 3,  Nick H M van Bakel 1,  Yusuke Maeda 9,  Richard J Rodenburg 3 10,  Maciej Adamowicz 11,  Ellen Crushell 12,  Hans Koenen 13,  Darius Adams 14,  Julia Vodopiutz 15,  Susanne Greber-Platzer 15,  Thomas Müller 16,  Gregor Dueckers 17,  Eva Morava 18 19 20,  Jolanta Sykut-Cegielska 21,  Gerard J M Martens 1,  Ron A Wevers 3,  Tim Niehues 17,  Martijn A Huynen 22,  Joris A Veltman 6 23,  Tom H Stevens 4,  Dirk J Lefeber 2 3
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
  • 3 Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
  • 4 Department of Chemistry and Biochemistry, Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA.
  • 5 Metabolic Unit, Rambam Health Care Center, Rappaport School of Medicine, Technion, 3109601 Haifa, Israel.
  • 6 Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Centre for Neuroscience, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
  • 7 The Milman-David Biomedical Research Unit, 24 Hazevi Avenue, 34355 Haifa, Israel.
  • 8 Department of Laboratory Medicine and Pathology, Mayo College of Medicine, Rochester, Minnesota 55905, USA.
  • 9 Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
  • 10 Department of Pediatrics, Nijmegen Centre for Mitochondrial Disorders (NCMD), Radboud university medical center, 6525 GA Nijmegen, The Netherlands.
  • 11 Protein Laboratory, Children's Memorial Health Institute, 04730 Warsaw, Poland.
  • 12 Temple Street Children's University Hospital, Temple Street, Dublin 1, DC01 YC67, Ireland.
  • 13 Department of Laboratory Medicine, Medical Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
  • 14 Personalized Genomic Medicine Pediatric Genetics and Metabolism Goryeb Children's Hospital, Morristown, New Jersey 07960, USA.
  • 15 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, 1090 Vienna, Austria.
  • 16 Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  • 17 HELIOS Kliniken Krefeld, Children's Hospital, Lutherplatz 40, 47805 Krefeld, Germany.
  • 18 Department of Pediatrics, Tulane University Medical School, New Orleans, Los Angeles 70112, USA.
  • 19 Department of Pediatrics, University Medical School of Leuven, 3000 Leuven, Belgium.
  • 20 Department of Pediatrics, Radboudumc, 6525GA, Nijmegen, The Netherlands.
  • 21 Screening Department, Institute of Mother and Child, 01-211 Warsaw, Poland.
  • 22 Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands.
  • 23 Department of Clinical Genetics, Maastricht University Medical Centre, 6229HX Maastricht, The Netherlands.
PMID: 27231034 DOI: 10.1038/ncomms11600
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.

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