ATP7A

ATP7A is a copper-transporting P-type ATPase encoded by the ATP7A gene on the X chromosome. It functions as a large transmembrane protein with an N-terminal region containing copper-binding domains and eight transmembrane segments that form the copper transport pathway. The protein cycles between the trans-Golgi network and other cellular compartments in response to cellular copper levels, delivering copper to copper-dependent enzymes in the secretory pathway and exporting excess copper when necessary. Copper is delivered to ATP7A by cytosolic copper chaperones such as ATOX1.

Biological role and regulation

In low copper conditions, ATP7A resides in the Golgi apparatus to supply copper to enzymes such as lysyl oxidase and ceruloplasmin within the secretory pathway. Under high copper or stress conditions, ATP7A traffics to the plasma membrane to facilitate copper efflux from cells, helping to maintain copper homeostasis. Proper function of ATP7A is essential for the maturation of several copper-dependent enzymes and for normal connective tissue formation and neurological development.

Clinical significance

Mutations in ATP7A cause Menkes disease, an X-linked recessive disorder characterized by severe copper deficiency in multiple tissues, leading to neurodegeneration, developmental delay, hypotonia, distinctive sparse, kinky hair, and characteristic facial features. Serum copper and ceruloplasmin levels are typically low. A milder complementation defect in ATP7A can produce Occipital horn syndrome, with connective tissue and skeletal abnormalities but less severe neurodevelopmental impairment. Diagnosis is through genetic testing and biochemical assays. Treatment, when started early, may include parenteral copper histidine, but response varies and is often limited; supportive care is important. ATP7A is related functionally to ATP7B, another copper-transporting ATPase involved in Wilson disease, but ATP7B primarily mediates biliary copper excretion in the liver.