Intracellular localization and loss of copper responsiveness of Mnk, the murine homologue of the Menkes protein, in cells from blotchy (Mo-blo) and brindled (Mo-br) mouse mutants

Menkes disease is an X-linked copper deficiency disorder that results from mutations in the A TP7A (MNK) gene, A wide range of disease-causing mutatio ns within ATP7A have been described, which lead to a diversity of phenotype s exhibited by Menkes patients, The mottled locus ((Mo, Atp7a, Mnk) represe nts the murine homologue of the A TP7A gene, and the mottled mutants exhibi t a diversity of phenotypes similar to that observed among Menkes patients, Therefore, these mutants are valuable models for studying Menkes disease, Two of the mottled mutants are brindled and blotchy and their phenotypes re semble classical Menkes disease and occipital horn syndrome (OHS) in humans , respectively. That is, the brindled mutant and patients with classical Me nkes disease are severely copper deficient and have profound neurological p roblems, while OHS patients and the blotchy mouse have a much milder phenot ype with predominantly connective tissue defects. In this study, in an atte mpt to understand the basis for the brindled and blotchy phenotypes, the co pper transport characteristics and intracellular distribution of the Mnk pr otein were assessed in cultured cells from these mutants. The results demon strated that the abnormal copper metabolism of brindled and blotchy cells m ay be related to a number of factors, which include the amount of Mnk prote in, the intracellular location of the protein and the ability of Mnk to red istribute in elevated copper, The data also provide evidence for a relation ship between the copper transport function and copper-dependent trafficking of Mnk.