The skins elastic fiber system consists of elastin (which is normally non-glycosylated) and glycosylated proteins (fibulin, fibronectin, and collagen). It is speculated that either abnormal glycosylation and/or impaired secretion of proteins caused by ATP6V0A2 dysfunction lead to WSS. The ATP6V0A2 pump is highly expressed within the Golgi apparatus. ATP6V0A2 is primarily found within the medial-Golgi and the trans-Golgi. ATP6V0A2 acidifies the medial- and trans-Golgi so that their resident enzymes (e.g. glycosidases and glycosyltransferases) function properly. Therefore, mutations in the ATP6V0A2 gene reduce the ability of ATP6V0A2 to produce the necessary pH gradient for these glycosylation enzymes, which results in abnormal N- and O-linked glycosylation. Because the physical properties of skin rely heavily on the structural proteins of the elastic fiber system of epidermal cells, abnormal glycosylation can lead to structural defects in the elastic fibers, and therefore lead to the inelastic skin seen in WSS. WSS patients may also have defective secretion of another ECM component of the skin called tropoelastin. The process of secreting tropoelastin from the cell is dependent on the acidic pH of vesicles. It is thought that increased pH levels (lower acidity) lead to the premature aggregation (coacervation) of tropoelastin inside the vesicle. The process of coacervation is thought to be essential for proper elastin assembly in the ECM. Coacervation must occur outside of the cell within the ECM ( the ECM has a more alkaline environment than the vesicle) for proper elastic fiber assembly.
Epidermal samples from the same patient subjected to electron microscopy revealed that elastin fibers display abnormally high levels of fragmentation and clumping of microfibrils, with little amorphous elastin. Within collagen bundles, collagen fibrils are of irregular shape and thickness. These disruptions of the patients connective tissue play a role in the inelasticity of the skin and wrinkling. Mechanism
Importance of the ATP6V0A2 pump
Vacuolar ATPases (V-ATPase) regulate the pH of the subcellular compartments found within the endosomal membrane system. V-ATPases are multiprotein complexes composed of two functional domains, a V0 domain, and a V1 domain. The V1 domain catalyzes the hydrolysis of ATP in order to power the pumping of protons through the V0 channel, which spans the lipid bilayer of endosomal compartments. Vacuolar ATPases are also localized within the plasma membrane of both renal cells and osteoclasts. In osteoclasts, V-ATPases are required for pumping protons onto the bone surface. The protons are then used for bone resorption. In renal cells, V-ATPases are used to pump protons into the urine. This facilitates bicarbonate reabsorption into the blood. The ATP6V0A2 gene encodes the a2 isoform of the a-subunit (present in the V0 domain). The a2 subunit anchors the V-ATPase to the membrane, and it is also directly involved with proton transport. ATP6V0A2 is encoded by the ATP6V0A2 gene. The ATP6V0A2 pump is found in virtually all cells and is thought to play an important role in the process of vesicular fusion in the secretory pathway, including the secretion of extracellular matrix components.