Human Molecular Genetics, Vol 7, 1245-1252, Copyright © 1998 by Oxford University Press
MJ Francis, EE Jones, ER Levy, S Ponnambalam, J Chelly and AP Monaco
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.
ARTICLES
A Golgi localization signal identified in the Menkes recombinant protein
Wellcome Trust Centre for Human Genetics, Windmill Road, Headington, Oxford OX3 7BN, UK.
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