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

Jansen, Erik; Timal, Sharita; Ryan, M. Dominic; Ashikov, Angel; Scherpenzeel, Monique van; Graham, Laurie A.; Mandel, Hanna; Hoischen, Alexander; Iancu, Theodore C.; Raymond, Kimiyo; Steenbergen, Gerry; Gilissen, Christian; Huijben, Karin; Bakel, Nick H.M. van; Maeda, Yusuke; Rodenburg, Richard J.; Adamowicz, Maciej; Crushell, Ellen; Koenen, Hans J. P. M.; Adams, Darius; Vodopiutz, Julia; Greber‐Platzer, Susanne; Müller, Thomas; Dueckers, G; Morava, Éva; Sykut-Cegielska, Jolanta; Martens, Gerard J.M.; Wevers, Ron A.; Niehues, Tim; Huynen, Martijn A.; Veltman, Joris A.; Stevens, Tom H.; Lefeber, Dirk

doi:10.1038/ncomms11600

Cited by 118 publications

(153 citation statements)

References 64 publications

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“…Finally, varying degrees of hypogammaglobulinemia with loss of antibody, are also noted in a number of disease with additional organ, metabolic or developmental defects ( 163 tetratricopeptide repeat domain 37 (TTC37), 164 and ATPase H+ transporting accessory protein 1 (ATP6AP1) deficiency 165 and phospholipase C, gamma-2 (PLCG2). 166…”

Section: Hypogammaglobulinemia With Syndromic Featuresmentioning

confidence: 99%

Common variable immune deficiency: Dissection of the variable

Cunningham‐Rundles

2018

Immunological Reviews

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Summary Starting about 60 years ago, a number of reports appeared that outlined the severe clinical course of a few adult subjects with profound hypogammaglobinemia. Puzzled by the lack of family history and adult onset of symptoms in most, the name “acquired” hypogammaglobinemia was given, but later altered to the current name common variable immune deficiency (CVID). Pathology reports remarked on the loss of lymph node architecture and paucity of plasma cells in lymphoid tissues in these subjects. While characterized by reduced serum IgG and IgA and often IgM, and thus classified amongst the B cell defects, an increasing number of cellular defects in these patients have been recognized over time. In the early years, severe respiratory tract infections commonly led to a shortened life span, but the wide spread availability of immune globulin concentrates for the last 25 years has improved survival. However, chronic non-infectious inflammatory and autoimmune conditions have now emerged as challenging clinical problems; these require further immunologic understanding and additional therapeutic measures. Recent study of this phenotypic syndrome have provided an increasingly fertile ground for the identification of autosomal recessive and now more commonly, autosomal dominant gene defects which lead to the loss of B cell development in this syndrome.

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Section: Hypogammaglobulinemia With Syndromic Featuresmentioning

confidence: 99%

Common variable immune deficiency: Dissection of the variable

Cunningham‐Rundles

2018

Immunological Reviews

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“…Of note, proteomics studies on purified SVs have also revealed the presence of ATP6AP1 (ATPase H + Transporting Accessory Protein 1, also known as Ac45) and ATP6AP2 (ATPase H + Transporting Accessory Protein 2, also known as the (pro)renin receptor/PRR) . Those two brain‐enriched trans‐membrane proteins are accessory components of the vATPase with some additional cellular functions—for example, ATP6AP1 is involved in the vATPase transport and exocytosis, and ATP6AP2 is reported to be essential for biogenesis of active vATPases . ATP6AP2 is also ideally posed to link vATPase to cell signaling, for example, the renin‐angiotensin system for regulating blood pressure and electrolyte balance, as well as Wnt signaling during embryo development .…”

Section: Mechanisms Of Sv (Re)acidificationmentioning

confidence: 99%

“…Of note, knock‐outs of the essential vATPase subunits are lethal, as well as of accessory subunit ATP6AP1, making the studies of these proteins difficult. If not lethal, a genetic perturbation of the vATPase subunits and accessory proteins ATP6AP1 and ATP6AP2 lead to inherited disorders …”

Section: Regulation Of the Vatpase Activity On The Synaptic Vesiclesmentioning

confidence: 99%

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Regulation of synaptic vesicle acidification at the neuronal synapse

Gowrisankaran

Milošević

2020

IUBMB Life

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The vacuolar H+‐adenosine triphosphatases (vATPases) acidify multiple intracellular organelles, including synaptic vesicles (SVs) and secretory granules. Acidification of SVs represents a critical point during the SV cycle: without acidification, neurotransmitters cannot be loaded into SVs. Despite the obvious importance of the vesicle acidification process for neurotrasmission and the life of complex organisms, little is known about the regulation of vATPase at the neuronal synapse. In addition, the composition of the vATPase complex on the SVs is unclear. Here, we summarize the key features of vATPase found on SVs, and propose a model of how vATPase activity is regulated during the SV cycle. It is anticipated that the information from the SV lumen is communicated to SV surface in order to signal successful acidification and neurotransmitter loading: we postulate here that the regulators of the vATPase activity exist (e.g., Rabconnectin‐3) that promote the recruitment of SV peripheral proteins and, consequently, SV fusion.

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“…Fourteen patients have been reported with the X‐linked ATP6AP1 deficiency (ATP6AP1‐CDG) . Key features were immunodeficiency and liver involvement .…”

Section: Introductionmentioning

confidence: 99%

ATP6AP1‐CDG: Follow‐up and female phenotype

et al. 2020

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In 2016, 11 male patients were reported with immunodeficiency and hepatic, gastric and (in some) neurological disease due to X-linked ATP6AP1 deficiency (ATP6AP1-CDG). In 2018, three other patients were reported with additional features: connective tissue abnormalities, sensorineural hearing loss, hyperopia, glomerular and tubular dysfunction, exocrine pancreatic insufficiency and altered amino acid and lipid metabolism. We here present a followup of three reported siblings showing progression of deafness to total hearing loss, progressive loss of hair up to alopecia, chestnut skin and, at last followup, in some of them proteinuria. Three female carriers showed a normal serum transferrin isoelectrofocusing but in two of them there was a persistent proteinuria. K E Y W O R D SATP6AP1 deficiency, congenital disorder of glycosylation, proteinuria

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

Cited by 118 publications

References 64 publications

Common variable immune deficiency: Dissection of the variable

Common variable immune deficiency: Dissection of the variable

Regulation of synaptic vesicle acidification at the neuronal synapse

ATP6AP1‐CDG: Follow‐up and female phenotype

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