TY - JOUR
T1 - ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation
AU - Jansen, Eric J.R.
AU - Timal, Sharita
AU - Ryan, Margret
AU - Ashikov, Angel
AU - Van Scherpenzeel, Monique
AU - Graham, Laurie A.
AU - Mandel, Hanna
AU - Hoischen, Alexander
AU - Iancu, Theodore C.
AU - Raymond, Kimiyo
AU - Steenbergen, Gerry
AU - Gilissen, Christian
AU - Huijben, Karin
AU - Van Bakel, Nick H.M.
AU - Maeda, Yusuke
AU - Rodenburg, Richard J.
AU - Adamowicz, Maciej
AU - Crushell, Ellen
AU - Koenen, Hans
AU - Adams, Darius
AU - Vodopiutz, Julia
AU - Greber-Platzer, Susanne
AU - Müller, Thomas
AU - Dueckers, Gregor
AU - Morava, Eva
AU - Sykut-Cegielska, Jolanta
AU - Martens, Gerard J.M.
AU - Wevers, Ron A.
AU - Niehues, Tim
AU - Huynen, Martijn A.
AU - Veltman, Joris A.
AU - Stevens, Tom H.
AU - Lefeber, Dirk J.
N1 - Funding Information:
This work was financially supported by the Institute of Genetic and Metabolic Disease (IGMD) (grant to D.J.L., R.R. and J.V.), by grants from the Dutch Organisation for Scientific Research, ZONMW-NWO (Medium Investment grant 40-00506-98-9001 and VIDI grant 91713359 to D.J.L.) and by National Institutes of Health grant GM38006 to T.H.S.
PY - 2016/5/27
Y1 - 2016/5/27
N2 - 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.
AB - 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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U2 - 10.1038/ncomms11600
DO - 10.1038/ncomms11600
M3 - Article
C2 - 27231034
AN - SCOPUS:84971238702
SN - 2041-1723
VL - 7
JO - Nature communications
JF - Nature communications
M1 - 11600
ER -