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Citation
Rujano, M.A., Cannata Serio, M., Panasyuk, G., Péanne, R., Reunert, J., Rymen, D., Hauser, V., Park, J.H., Freisinger, P., Souche, E., Guida, M.C., Maier, E.M., Wada, Y., Jäger, S., Krogan, N.J., Kretz, O., Nobre, S., Garcia, P., Quelhas, D., Bird, T.D., Raskind, W.H., Schwake, M., Duvet, S., Foulquier, F., Matthijs, G., Marquardt, T., Simons, M. (2017). Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects.  J. exp. Med. 214(12): 3707--3729.
FlyBase ID
FBrf0237364
Publication Type
Research paper
Abstract

The biogenesis of the multi-subunit vacuolar-type H+-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V-ATPase subunit ATP6AP2 (also known as the prorenin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into Drosophila led to reduced survival and altered lipid metabolism. We further demonstrate that in the liver-like fat body, the autophagic dysregulation was associated with defects in lysosomal acidification and mammalian target of rapamycin (mTOR) signaling. Finally, both ATP6AP2 mutations impaired protein stability and the interaction with ATP6AP1, a member of the V0 assembly complex. Collectively, our data suggest that the missense mutations in ATP6AP2 lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy.

PubMed ID
PubMed Central ID
PMC5716037 (PMC) (EuropePMC)
Related Publication(s)
Note

Mutations in ATP6AP2 cause autophagic liver disease in humans.
Cannata Serio et al., 2018, Autophagy 14(6): 1088--1089 [FBrf0239738]

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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    J. exp. Med.
    Title
    Journal of Experimental Medicine
    Publication Year
    1896-
    ISBN/ISSN
    0022-1007
    Data From Reference