ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation.
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Jansen EJ, Timal S, Ryan M, Ashikov A, van Scherpenzeel M, Graham LA, Mandel H, Hoischen A, Iancu TC, Raymond K, Steenbergen G, Gilissen C, Huijben K, van Bakel NH, Maeda Y, Rodenburg RJ, Adamowicz M, Crushell E, Koenen H, Adams D, Vodopiutz J, Greber-Platzer S, Muller T, Dueckers G, Morava E, Sykut-Cegielska J, Martens GJ, Wevers RA, Niehues T, Huynen MA, Veltman JA, Stevens TH, Lefeber DJ
ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation.
Nat Commun. 2016 May 27;7:11600. doi: 10.1038/ncomms11600.
- PubMed ID
- 27231034 [ View in PubMed]
- 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 approximately 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.