ATP6V0A2

Cutis laxa

More than 40 variants (also known as mutations) in the ATP6V0A2 gene have been identified in people with cutis laxa. ATP6V0A2 variants cause a form of the disorder called autosomal recessive cutis laxa type 2A (ARCL2A), which is characterized by loose, sagging skin; distinctive facial features; and larger than normal spaces (fontanelles) between the skull bones that close later than usual. Some affected individuals also have delayed development, intellectual disability, seizures, or problems with movement that can worsen over time. Variants in this gene also cause a related condition called wrinkly skin syndrome, which typically has milder features. 

Variants in the ATP6V0A2 gene prevent the cell from producing a functional a2 subunit, which disrupts the normal function of V-ATPases. It is unclear how these genetic changes cause the signs and symptoms of cutis laxa. Researchers suspect that changes in V-ATPase function may disrupt the normal glycosylation of proteins, including several that are involved in the assembly and maintenance of elastic fibers. Elastic fibers are slender bundles of proteins that provide strength and flexibility to connective tissue (tissue that supports the body's joints and organs). People with cutis laxa have a reduced density of elastic fibers, which weakens connective tissue in the skin, lungs, and other organs. These defects in connective tissue underlie many of the major features of the disorder.

Because problems with glycosylation underlie ARCL2A, the condition is classified as a congenital disorder of glycosylation.