Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects

Rujano MA, Serio MC, Panasyuk G, P RA, Reunert J, Rymen D, Hauser V, Park JH, Freisinger P, Souche E, Guida MC, et al. (2017)
JOURNAL OF EXPERIMENTAL MEDICINE 214(12): 3707-3729.

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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 [pro]renin 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.
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Rujano MA, Serio MC, Panasyuk G, et al. Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. JOURNAL OF EXPERIMENTAL MEDICINE. 2017;214(12):3707-3729.
Rujano, M. A., Serio, M. C., Panasyuk, G., P, R. A., Reunert, J., Rymen, D., Hauser, V., et al. (2017). Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. JOURNAL OF EXPERIMENTAL MEDICINE, 214(12), 3707-3729. doi:10.1084/jem.20170453
Rujano, M. A., Serio, M. C., Panasyuk, G., P, R. A., Reunert, J., Rymen, D., Hauser, V., Park, J. H., Freisinger, P., Souche, E., et al. (2017). Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. JOURNAL OF EXPERIMENTAL MEDICINE 214, 3707-3729.
Rujano, M.A., et al., 2017. Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. JOURNAL OF EXPERIMENTAL MEDICINE, 214(12), p 3707-3729.
M.A. Rujano, et al., “Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects”, JOURNAL OF EXPERIMENTAL MEDICINE, vol. 214, 2017, pp. 3707-3729.
Rujano, M.A., Serio, M.C., Panasyuk, G., P, R.A., Reunert, J., Rymen, D., Hauser, V., Park, J.H., Freisinger, P., Souche, E., Guida, M.C., Maier, E.M., Wada, Y., Jager, 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.: Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects. JOURNAL OF EXPERIMENTAL MEDICINE. 214, 3707-3729 (2017).
Rujano, Maria A., Serio, Magda Cannata, Panasyuk, Ganna, P, Romain Anne, Reunert, Janine, Rymen, Daisy, Hauser, Virginie, Park, Julien H., Freisinger, Peter, Souche, Erika, Guida, Maria Clara, Maier, Esther M., Wada, Yoshinao, Jager, Stefanie, Krogan, Nevan J., Kretz, Oliver, Nobre, Susana, Garcia, Paula, Quelhas, Dulce, Bird, Thomas D., Raskind, Wendy H., Schwake, Michael, Duvet, Sandrine, Foulquier, Francois, Matthijs, Gert, Marquardt, Thorsten, and Simons, Matias. “Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects”. JOURNAL OF EXPERIMENTAL MEDICINE 214.12 (2017): 3707-3729.
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