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; Julia Vodopiutz; Susanne Greber-Platzer; Thomas Mueller; 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

doi:10.1038/ncomms11600

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 AdamsJulia Vodopiutz, Susanne Greber-Platzer, Thomas Mueller, 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 B40-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 language	English
Article number	11600
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11600
Publication status	Published - May 2016

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Jansen, E. J. R., Timal, S., Ryan, M., Ashikov, A., van Scherpenzeel, M., Graham, L. A., Mandel, H., Hoischen, A., Iancu, T. C., Raymond, K., Steenbergen, G., Gilissen, C., Huijben, K., van Bakel, N. H. M., Maeda, Y., Rodenburg, R. J., Adamowicz, M., Crushell, E., Koenen, H., ... Lefeber, D. J. (2016). ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nature Communications, 7, Article 11600. https://doi.org/10.1038/ncomms11600

@article{636884854f3645e1af78b9987acd3eb2,

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

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 B40-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.",

author = "Jansen, {Eric J. R.} and Sharita Timal and Margret Ryan and Angel Ashikov and {van Scherpenzeel}, Monique and Graham, {Laurie A.} and Hanna Mandel and Alexander Hoischen and Iancu, {Theodore C.} and Kimiyo Raymond and Gerry Steenbergen and Christian Gilissen and Karin Huijben and {van Bakel}, {Nick H. M.} and Yusuke Maeda and Rodenburg, {Richard J.} and Maciej Adamowicz and Ellen Crushell and Hans Koenen and Darius Adams and Julia Vodopiutz and Susanne Greber-Platzer and Thomas Mueller and Gregor Dueckers and Eva Morava and Jolanta Sykut-Cegielska and Martens, {Gerard J. M.} and Wevers, {Ron A.} and Tim Niehues and Huynen, {Martijn A.} and Veltman, {Joris A.} and Stevens, {Tom H.} and Lefeber, {Dirk J.}",

year = "2016",

month = may,

doi = "10.1038/ncomms11600",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

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, Mueller, 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

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 - Mueller, 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

Y1 - 2016/5

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 B40-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 B40-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.

U2 - 10.1038/ncomms11600

DO - 10.1038/ncomms11600

M3 - Article

C2 - 27231034

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11600

ER -

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

Abstract

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