Distinct phenotype of a Wilson disease mutation reveals a novel trafficking determinant in the copper transporter ATP7B

Significance Wilson disease (WD) is a disorder of copper overload whose variable presentation poses diagnostic and treatment challenges. WD is caused by mutations in ATP7B, a transporter that loads Cu(I) onto newly synthesized cupro-enzymes in thetrans -Golgi network (TGN) and exports excess copper by trafficking from the TGN to the plasma membrane. This multidisciplinary study established that a patient mutation, ATP7B-S653Y, has Cu(I) transport activity in the TGN, but completely disrupts Cu(I)-responsive trafficking. ATP7B-S653Y perturbs long-range interdomain interactions mediated by transmembrane segments TM1/TM2, suggesting a new functional role for this region. ATP7B-S653Y is the best-characterized example of a new functional class of WD mutants. We suggest that functional classification of WD mutations may facilitate targeted therapy for patients.