Wilson disease causing mutations in the carboxyl terminus of ATP7B regulates its localization and golgi exit selectively in the unpolarized cells.

Mutational inactivation of the P-type Cu-ATPase ATP7B interferes with its cellular functions to varying extent leading to varied cellular phenotypes. Wilson's Disease primarily affects organs composed of polarized/differentiated epithelial cells. Therefore, phenotypic variability might differ depending on the polarization/differentiation of the cells. The present study investigates the intracellular stability and localization of ATP7B harboring WD mutations in both unpolarized/undifferentiated and polarized/differentiated cell-based model. GFP-ATP7B harboring the WD causing mutations, N41S, S653Y, R778Q, G1061E, H1069Q, S1423N, S1426I and T1434M, are included for investigation. The C-terminal Wilson Disease mutations (S1423N, S1426I and T1434M), exhibit distinct localization and Cu(I) responsive anterograde and retrograde trafficking in undifferentiated/unpolarized versus differentiated/polarized cells. While basal localization of the S1423N mutant gets corrected in the differentiated glia, its Cu(I) responsive anterograde and retrograde trafficking behavior is not identical to the wildtype. But localization and trafficking properties are completely rescued for the S1426I and T1434M mutants in the differentiated cells. Comprehensive meta-analysis on the effect of the reported C-terminal mutations on patient phenotype and cultured cells demonstrate discrete regions having distinct effects. While mutations in the proximal C-terminus affect ATP7B stability, the present study shows that the distal region dictates cell specific TGN localization and exit. The localization and export properties are corrected in the differentiated cells which is a plausible mechanism for the milder phenotype exhibited by these mutations. It highlights the critical role of the C-terminus in cell specific TGN retention and exit of ATP7B.