Clinlab Navigator

ATP7B Mutation

The ATP7B gene on chromosome 13 is expressed mainly in hepatocytes and encodes the copper-transporting intracellular protein, called ATP7B. ATP7B is a P-type ATPase that binds copper at its N-terminal domain and is responsible for the transmembrane transport of copper using ATP as an energy source. ATP7B in the trans-Golgi network regulates the incorporation of six copper molecules into apoceruloplasmin to form ceruloplasmin. Ceruloplasmin is then secreted into the bloodstream, where it accounts for approximately 90 percent of the circulating copper. In the cytoplasmic vesicles, ATP7B-mediated copper transport sequesters excess copper in these pre-lysosomal vesicles, which are then excreted into bile via exocytosis across the hepatocyte apical canalicular membrane.

Mutations in ATP7B gene impair both the incorporation of copper into apoceruloplasmin and the excretion of copper into bile, the latter reducing the major pathway of hepatic copper elimination. The impairments in copper transport result in excess copper accumulation within hepatocytes. Excess copper is initially bound to metallothionein and distributed evenly throughout the cytoplasm. With progressive copper accumulation, the capacity of metallothionein is exceeded and hepatocyte injury occurs.

Wilson disease, also known as hepatolenticular degeneration, is an autosomal recessive disorder that is caused by a deficiency of ATP7B. As a result, copper accumulates first in the liver and then in brain, kidneys, bones, and corneas. Wilson disease affects approximately 1 in 30,000 people worldwide, with a carrier frequency of approximately 1 in 90 individuals. Patients with Wilson’s disease may present with chronic liver disease, acute liver failure, hemolysis, and psychiatric or neurologic manifestations. Viral infection or drug toxicity may serve as a trigger for fulminant Wilson’s disease.

A variety of laboratory tests are recommended in the initial evaluation for Wilson disease. In approximately 95% of cases, serum ceruloplasmin is below normal. Additionally, patients with Wilson disease show decreased copper in serum, increased copper in urine, and significantly elevated copper on liver biopsy.

The pathological diagnosis of Wilson’s disease is based on the presence of compatible histologic features and a positive copper stain. Unfortunately, the rhodanine stain does not always detect copper in the cytoplasm of hepatocytes. Copper quantification on either a dedicated core-biopsy specimen or a paraffin-embedded tissue block is considered to be the best available diagnostic test.

Over 500 different mutations in the ATP7B gene have been identified in patients with Wilson disease. The H1069Q mutation is one of the most common mutations, with an allelic frequency of 10 to 40 percent. Most patients are compound heterozygotes, carrying different mutations on each copy of chromosome 13. Mutation analysis may be helpful if routine tests are not diagnostic. Most mutations are family-specific with the exception of the H1069Q mutation, which accounts for >50% of identified disease alleles in the Northern European Caucasian population. Mutations are detected by PCR amplification of all 21 exons and a portion of the 5' untranslated region (UTR) followed by DNA sequencing.

Olson KR, et al. Case 2-2017 — An 18-Year-Old Woman with Acute Liver Failure. N Engl J Med 2017; 376:268-278January 19, 2017

 Gu YH, Kodama H, Du SL, et al: Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. Clin Genet 2003 Dec;64[6]:479-484)

Updated Articles

C1 Esterase Inhibitor

Hereditary angioedema is caused by a deficiency or dysfunction of C1 esterase inhibitor (C1-INH). C1 esterase inhibitor is a serum alpha-2 globulin and a member of the serpin family of protease inhibitors that is primarily synthesized by the liver.…

New Articles

Babesia microti

Babesiosis is a tickborne zoonotic disease that is caused primarily by the intraerythrocytic parasite Babesia in the United States. The first case of human babesiosis acquired in the United States was identified in 1969 on Nantucket Island,…

Blog

Quantity of…

SARS-CoV-2, the causative agent of COVID-19, spreads through exhaled breath during breathing, coughing, talking, and singing. Olfactory scientists at Northwestern University Feinberg School of Medicine developed a portable device for the collection…