Wrinkly skin syndrome

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.[6] Vacuolar ATPases are also localized within the plasma membrane of both renal cells and osteoclasts.[6] 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).[6] The a2 subunit anchors the V-ATPase to the membrane, and it is also directly involved with proton transport.[2] 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.[6]

The most important subcellular structure in the context of wrinkly skin syndrome (WSS), is the Golgi apparatus. The Golgi apparatus is an important part of the endomembrane system because it processes proteins and lipids prior to their delivery to the plasma membrane and/or secretion into the extracellular environment. The Golgi is organized into a polarized series of membrane-bound stacks, called cisternae, through which proteins are trafficked in sequence once they leave the endoplasmic reticulum (ER), where the proteins and lipids are synthesized. Proteins destined for secretion or delivery to the plasma membrane arrive first at the cis-Golgi, before being trafficked through the medial and trans-Golgi.[7] In the Golgi, proteins undergo extensive post-translational modifications (PTMs). In the context of WSS, the most significant PTM events are the glycosylation of proteins comprising the extracellular matrix (ECM) of epidermal cells. The two types of glycosylation events in the Golgi are N-linked glycosylation and O-linked glycosylation.[8] Glycosylation of proteins destined for secretion occurs through the forward movement of proteins throughout the Golgi apparatus. The proteins destined for secretion are then trafficked to the plasma membrane in secretory vesicles. Retrograde (backward) transport in the Golgi apparatus is also important. In order to retain the enzymes responsible for protein glycosylation in the correct regions of the Golgi, there must be retrograde transport of these enzymes back into the Golgi apparatus.[8] In addition, retrograde transport serves a quality control function, by shuttling misfolded proteins back into the ER or retaining them within the Golgi itself until proper protein folding and maturation is completed.[8] The activity of protein-modifying enzymes, like glycosyltransferases and glycosidases, relies on the lumenal pH of the Golgi apparatus.[8] Cisternal pH becomes increasingly acidic (lower pH) with progression from cis- to trans- regions of the Golgi.[8] Disruption of decreasing pH can impart significant effects on the efficiency and sequence of glycosylation events.[8] Maintenance of the pH gradient across the Golgi is instrumental for proper post-translational modification of proteins prior to secretion. Retrograde transport and pH regulation are therefore vital to the proper functioning of the Golgi apparatus.[8]

Patients with both missense and/or nonsense mutations of the ATP6V0A2 gene have been shown to phenotypically express wrinkly skin syndrome (WSS) or autosomal recessive cutis laxa type II (ARCL II) (another cutis laxa disorder).[6] Some consider WSS to be a milder variant of ARCL II, but the genetic causes of WSS are not yet known.[6] A large number of patients with WSS and ARCL II show a loss-of-function in the a2-subunit.[2] These mutations in ATP6V0A2 are associated with defective glycan biosynthesis and defective Golgi apparatus structure.[7] However, the exact mechanism of how mutations in the ATP6V0A2 gene lead to these effects is unclear.

WSS is characterized by defects in the elastic fiber system that comprises the extracellular matrix of epidermal cells.[6] The skin's 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.[6] The ATP6V0A2 pump is highly expressed within the Golgi apparatus.[7] 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.[7] 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.[9] The process of secreting tropoelastin from the cell is dependent on the acidic pH of vesicles.[9] It is thought that increased pH levels (lower acidity) lead to the premature aggregation (coacervation) of tropoelastin inside the vesicle.[9] The process of coacervation is thought to be essential for proper elastin assembly in the ECM.[9] 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.[9] However, defective ATP6V0A2 pumps in the vesicle increase the lumenal pH of the vesicle, leading to premature coacervation and defective elastic fiber assembly.[9] The abnormal assembly and glycosylation of proteins used to make elastic fibers explains the connective tissue phenotypes associated with ARCL2 and WSS but does not explain the neurodevelopmental disorders or growth defects of these patients (18). Elastin is not required for brain or bone growth.[10] However, it is believed that abnormal/impaired secretion of the brain and bone-specific ECM proteins caused by dysregulation of Golgi acidification is what leads to the neural and skeletal defects in ARCL2.[9]

Several symptoms are shared with cutis laxa type II (CLT2) including wrinkling of skin, microcephaly, and developmental delay which has made proper diagnosis difficult in several cases.[13] However, the severity of skin abnormalities and facial dysmorphia is greater in cutis laxa type II.[13]