ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation
Open Access
- 27 May 2016
- journal article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 7 (1), 11600
- https://doi.org/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.Keywords
This publication has 63 references indexed in Scilit:
- Integrative genomics viewerNature Biotechnology, 2011
- V-ATPase-Mediated Granular Acidification Is Regulated by the V-ATPase Accessory Subunit Ac45 in POMC-Producing CellsMolecular Biology of the Cell, 2010
- Regulation and Isoform Function of the V-ATPasesBiochemistry, 2010
- Next-Generation Sequencing of a 40 Mb Linkage Interval Reveals TSPAN12 Mutations in Patients with Familial Exudative VitreoretinopathyAmerican Journal of Human Genetics, 2010
- Voa1p Functions in V-ATPase Assembly in the Yeast Endoplasmic ReticulumMolecular Biology of the Cell, 2008
- Role of furin in granular acidification in the endocrine pancreas: Identification of the V-ATPase subunit Ac45 as a candidate substrateProceedings of the National Academy of Sciences of the United States of America, 2008
- Cytoplasmic Terminus of Vacuolar Type Proton Pump Accessory Subunit Ac45 Is Required for Proper Interaction with V0 Domain Subunits and Efficient Osteoclastic Bone ResorptionOnline Journal of Public Health Informatics, 2008
- Antigen presentation by B lymphocytes: how receptor signaling directs membrane traffickingCurrent Opinion in Immunology, 2007
- Mapping the Arabidopsis organelle proteomeProceedings of the National Academy of Sciences of the United States of America, 2006
- Predicting transmembrane protein topology with a hidden markov model: application to complete genomesJournal of Molecular Biology, 2001