Human Molecular Genetics, Vol 6, 1037-1042, Copyright © 1997 by Oxford University Press
A Grimes, CJ Hearn, P Lockhart, DF Newgreen and JF Mercer
The brindled mouse mutant (Mo(br)) is the closest animal model of the human
genetic copper deficiency, Menkes disease, which is presumed to be due to a
mutation at the X-linked mottled locus (Mo). The mutant mice are
hypopigmented and die at around 15 days after birth, but can be saved by
treatment with copper before the 10th postnatal day. Menkes disease has
been shown to be due to mutations of the gene ATP7A which encodes P-type
ATPase (referred to here as MNK). MNK is likely to function in copper
efflux from cells, but the full range of its biological activity is not
fully understood. The nature of the mutation in the brindled mouse is of
importance in our understanding of the role of MNK and for devising
treatment strategies for Menkes disease. Here we show that the brindled
mouse has a deletion of two amino acids in a highly conserved, but
functionally uncharacterized, region of Mnk. Comparison with the Ca ATPases
suggests this region may be involved in conformational changes associated
with the E1/E2 transition fundamental to the action of P-type ATPases. We
also describe the first Western blot data for Mnk in tissues, and these
show normal levels of Mnk in mutant and brindled kidneys but none in liver.
In the kidney, immunohistochemistry demonstrated Mnk in the proximal and
distal tubules, the distribution is identical in mutant and normal. This
distribution is consistent with Mnk being involved in copper resorption
from the urine.
ARTICLES
Molecular basis of the brindled mouse mutant (Mo(br)): a murine model of Menkes disease
Murdoch Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
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