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

• DOI: 10.1038/ncomms11600
• Publication Date: 2016-05-27T09:22:42Z
• Authors: Eric J. R. Jansen; Sharita Timal; Margret Ryan; Angel Ashikov; Monique van Scher...; 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-Pl...; Thomas Müller; Gregor Dueckers; Eva Morava; Jolanta Sykut-Ceg...; Gerard J. M. Martens; Ron A. Wevers; Tim Niehues; Martijn A. Huynen; Joris A. Veltman; Tom H. Stevens; Dirk J. Lefeber
• Keywords: Adult; Male; 0301 basic medicine; Vacuolar Proton-Translocating ATPases; Glycosylation; Adolescent; Science; Mutation, Missense; Article; Young Adult; 03 medical and health sciences; Humans; Cognitive Dysfunction; Amino Acid Sequence; Child; Family Health; Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience; Base Sequence; Sequence Homology, Amino Acid; Liver Diseases; Molecular Animal Physiology; Q; Immunologic Deficiency Syndromes; Infant; Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience; Child, Preschool; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life Sciences

AbstractThe 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.