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

Eric J.R. Jansen, Sharita Timal, Margret Ryan, Angel Ashikov, Monique Van Scherpenzeel, 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 & 13 others Julia Vodopiutz, Susanne Greber-Platzer, Thomas Müller, Gregor Dueckers, Eva Morava, Jolanta Sykut-Cegielska, Gerard J.M. Martens, Ron A. Wevers, Tim Niehues, Martijn A. Huynen, Joris A. Veltman, Tom H. Stevens, Dirk J. Lefeber

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Article number11600
JournalNature Communications
Volume7
DOIs
StatePublished - May 27 2016

Fingerprint

Glycosylation
yeast
impairment
Adenosine Triphosphatases
assembly
proteins
Yeast
causes
Yeasts
Proteins
phenotype
accessories
regulators
homology
abnormalities
mutations
liver
brain
Agammaglobulinemia
coding

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Jansen, E. J. R., Timal, S., Ryan, M., Ashikov, A., Van Scherpenzeel, M., Graham, L. A., ... Lefeber, D. J. (2016). ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nature Communications, 7, [11600]. https://doi.org/10.1038/ncomms11600
Jansen, Eric J.R. ; Timal, Sharita ; Ryan, Margret ; Ashikov, Angel ; Van Scherpenzeel, Monique ; Graham, Laurie A. ; Mandel, Hanna ; Hoischen, Alexander ; Iancu, Theodore C. ; Raymond, Kimiyo ; Steenbergen, Gerry ; Gilissen, Christian ; Huijben, Karin ; Van Bakel, Nick H.M. ; Maeda, Yusuke ; Rodenburg, Richard J. ; Adamowicz, Maciej ; Crushell, Ellen ; Koenen, Hans ; Adams, Darius ; Vodopiutz, Julia ; Greber-Platzer, Susanne ; Müller, Thomas ; Dueckers, Gregor ; Morava, Eva ; Sykut-Cegielska, Jolanta ; Martens, Gerard J.M. ; Wevers, Ron A. ; Niehues, Tim ; Huynen, Martijn A. ; Veltman, Joris A. ; Stevens, Tom H. ; Lefeber, Dirk J. / ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. In: Nature Communications. 2016 ; Vol. 7.
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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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Jansen, EJR, 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, NHM, Maeda, Y, Rodenburg, RJ, Adamowicz, M, Crushell, E, Koenen, H, Adams, D, Vodopiutz, J, Greber-Platzer, S, Müller, T, Dueckers, G, Morava, E, Sykut-Cegielska, J, Martens, GJM, Wevers, RA, Niehues, T, Huynen, MA, Veltman, JA, Stevens, TH & Lefeber, DJ 2016, 'ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation', Nature Communications, vol. 7, 11600. https://doi.org/10.1038/ncomms11600

ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. / Jansen, Eric J.R.; Timal, Sharita; Ryan, Margret; Ashikov, Angel; Van Scherpenzeel, Monique; Graham, Laurie A.; Mandel, Hanna; Hoischen, Alexander; Iancu, Theodore C.; Raymond, Kimiyo; Steenbergen, Gerry; Gilissen, Christian; Huijben, Karin; Van Bakel, Nick H.M.; Maeda, Yusuke; Rodenburg, Richard J.; Adamowicz, Maciej; Crushell, Ellen; Koenen, Hans; Adams, Darius; Vodopiutz, Julia; Greber-Platzer, Susanne; Müller, Thomas; Dueckers, Gregor; Morava, Eva; Sykut-Cegielska, Jolanta; Martens, Gerard J.M.; Wevers, Ron A.; Niehues, Tim; Huynen, Martijn A.; Veltman, Joris A.; Stevens, Tom H.; Lefeber, Dirk J.

In: Nature Communications, Vol. 7, 11600, 27.05.2016.

Research output: Contribution to journalArticle

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.

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

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JO - Nature Communications

JF - Nature Communications

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