Wilson disease protein

Copper metabolism

Structure of ATP7B

Wilson disease protein (also known as ATP7B) is a protein that plays a critical role in the regulation of copper levels within the body. It is encoded by the ATP7B gene in humans. Mutations in this gene are responsible for the onset of Wilson's disease, a rare autosomal recessive genetic disorder characterized by excessive accumulation of copper in the body's tissues, leading to neurological symptoms, liver disease, and psychiatric problems.

Function

The Wilson disease protein is a copper-transporting ATPase, which is primarily found in the liver, brain, kidneys, and placenta. Its main function is to facilitate the excretion of copper into the bile and to incorporate copper into ceruloplasmin, a glycoprotein that carries copper in the blood. By regulating copper levels, ATP7B ensures that the body maintains a necessary but not toxic concentration of this essential mineral.

Genetic and Molecular Basis

The ATP7B gene is located on chromosome 13 (13q14.3) and consists of 21 exons. Mutations in ATP7B can lead to Wilson's disease, with over 500 mutations identified to date, including missense mutations, nonsense mutations, and insertions or deletions. These genetic alterations disrupt the normal function of the Wilson disease protein, leading to impaired copper transport and accumulation of copper in tissues.

Pathophysiology

In individuals with Wilson's disease, the dysfunction of ATP7B results in reduced incorporation of copper into ceruloplasmin and decreased excretion of copper into bile. This leads to copper accumulation in the liver, causing liver damage and, eventually, liver failure. Excess copper can also accumulate in the brain, particularly in the basal ganglia, causing neurological symptoms such as tremors, poor coordination, and cognitive decline. Other organs, including the kidneys, eyes (leading to Kayser-Fleischer rings), and heart, can also be affected.

Clinical Manifestations

Wilson's disease can present with a wide range of symptoms, depending on the organs affected. Liver-related symptoms may include fatigue, abdominal pain, jaundice, and signs of chronic liver disease. Neurological symptoms can range from movement disorders, such as tremors and ataxia, to psychiatric symptoms like depression and anxiety. The presence of Kayser-Fleischer rings, a golden-brown discoloration of the cornea, is a hallmark diagnostic feature.

Diagnosis and Treatment

Diagnosis of Wilson's disease involves a combination of clinical evaluation, biochemical tests (including serum ceruloplasmin levels, liver function tests, and copper levels in the blood and urine), and genetic testing for mutations in the ATP7B gene. Imaging studies, such as MRI of the brain, may also be used to assess neurological involvement.

Treatment focuses on reducing copper accumulation and preventing further damage. Medications such as D-penicillamine, trientine, and zinc acetate are commonly used to chelate copper or inhibit its absorption. In severe cases, particularly those involving acute liver failure, liver transplantation may be necessary.

Prognosis

With early diagnosis and appropriate treatment, individuals with Wilson's disease can often lead normal lives. However, untreated or inadequately managed Wilson's disease can lead to serious complications, including irreversible liver or brain damage and death.