In Wilson's disease, copper accumulates in the liver, brain, and cornea (Kayser-Fleischer rings). What is the PRIMARY biochemical defect responsible for copper accumulation?
- A Deficiency of ceruloplasmin causing poor copper transport
- B Excess dietary copper absorption through DMT-1 upregulation
- C Mutation in ATP7B, a copper-transporting ATPase in hepatocytes, impairing biliary copper excretion ✓
- D Deficiency of metallothionein in hepatocytes
Explanation
Wilson's disease is caused by autosomal recessive mutations in ATP7B (chromosome 13), encoding a copper-transporting P-type ATPase located in the trans-Golgi network of hepatocytes. ATP7B normally incorporates copper into ceruloplasmin and exports excess copper into bile for excretion. With non-functional ATP7B, biliary copper excretion fails; copper accumulates first in hepatocytes (hepatitis, cirrhosis), then overflows into blood (free copper — not bound to ceruloplasmin), deposits in basal ganglia and cornea. Ceruloplasmin may be low secondarily but is not the primary defect.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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