Renin receptor
endoplasmic reticulum membrane
Mutations in the X-linked <i>ATP6AP2</i> cause a glycosylation disorder with autophagic defects.
The biogenesis of the multi-subunit vacuolar-type H<sup>+</sup>-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 <i>ATP6AP2</i> deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects. The introduction of one of the missense mutations into <i>Drosophila</i> 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 <i>ATP6AP2</i> 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 <i>ATP6AP2</i> lead to impaired V-ATPase assembly and subsequent defects in glycosylation and autophagy.