Menkes disease arises from a genetic impairment in
copper transport. The gene responsible for the phenotype has been identified as a
copper transporting ATPase ( ATP7A ). Recently, the
protein encoded by the ATP7A gene has been localized to the Golgi complex. In order to investigate the role of the
Menkes disease protein in
copper transport, recombinant constructs containing both the full-length open reading frame and an alternatively spliced form have been successfully expressed and localized in mammalian cells. Other studies of a patient with
occipital horn syndrome, an allelic variant of
Menkes disease, have demonstrated that only this alternatively spliced
isoform and not the full-length form is expressed in this patient. The milder form of this patient's phenotype suggests that the alternatively spliced
isoform has some functional role in
copper transport. In the present study the full-length recombinant Menkes
protein was shown by immunofluorescence to localize to the Golgi apparatus and the alternatively spliced form, lacking sequences for transmembrane domains 3 and 4 encoded by exon 10, was shown to localize to the endoplasmic reticulum. Using sequences from exon 10 fused to a non-Golgi reporter molecule, a 38 amino acid sequence containing transmembrane domain 3 of the Menkes
protein was found to be sufficient for localization to the Golgi complex. Therefore, the
protein sequence encoded by exon 10 may be responsible for this differential localization and both
isoforms may be required for comprehensive transport of
copper within the cell.