Human Molecular Genetics, Vol 8, 1547-1555, Copyright © 1999 by Oxford University Press
L Ambrosini and JF Mercer
Menkes disease is an X-linked disorder of copper metabolism. An overall
copper deficiency reduces the activity of copper-dependent enzymes
accounting for the clinical presentation of affected individuals. The
Menkes gene product (MNK) is a P-type ATPase and is considered to be the
main copper efflux protein in most cells. The protein is located primarily
at the trans -Golgi network (TGN), but relocalizes to the plasma membrane
in elevated copper conditions to expel the excess copper from the cell.
Here we report the first missense mutation which causes mild Menkes
disease, a mutation in a successfully copper-treated classical Menkes
patient and the effect of each mutation on the localization of MNK within
the cell. Using western blot analysis, MNK was detectable in cells from
both patients, but appeared to be mislocalized in the treated case. In the
mild Menkes patient, the protein appeared to be located in the TGN but
failed to redistribute towards the cell periphery in response to copper.
This is the first description of a mutation in a Menkes patient which
affects the trafficking of MNK, and the loss of this process is consistent
with the clinical phenotype.
ARTICLES
Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper-treated classical Menkes disease
The Murdoch Institute, Royal Children's Hospital, Flemington Road, Parkville 3052, Australia.
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