Human Molecular Genetics, Vol 5, 1619-1624, Copyright © 1996 by Oxford University Press
MB Theophilos, DW Cox and JF Mercer
Wilson disease (WD) is an autosomal recessive defect of copper transport
characterized by massive accumulation of copper in the liver, which can
lead to liver failure. Mutations in a copper transporting ATPase (WND or
ATP7B) have been shown to cause the disease. The toxic milk mouse mutant
(tx) accumulates copper in the liver in a manner similar to that observed
in patients with WD. However, some physiological differences between tx
mice and human WD patients have cast doubts on whether this mutant mouse is
a valid model for WD. In this paper we report the isolation of cDNA clones
encoding the murine homologue of WND. The predicted amino acid sequence is
1462 amino acids and contains the same functional domains identified in
human and rat WND. As in the rat, the fourth metal binding domain is
apparently non- functional. Similar levels of a 7.5 kb WND mRNA were
detected in liver and kidney from normal and tx mice, indicating that
transcription of this gene was unaffected in the mutant mice. The coding
sequence of WND cDNA from the tx mouse liver identified a single nucleotide
difference between the normal DL mouse and the tx which is predicted to
change methionine 1356 in the eighth transmembrane domain to valine. This
methionine is conserved in all copper ATPases including those from bacteria
and yeast. The conclusion that this is the causative mutation is supported
by the recent mapping of tx and WND to the same region of mouse chromosome
8. Thus the tx mouse is presented as a valid model for studies of the role
of WND in copper transport and for investigation of different treatment
strategies for WD.
ARTICLES
The toxic milk mouse is a murine model of Wilson disease
Scobie and Clare Mackinnon Trace Element Laboratory, Murdoch Institute, Royal Children's Hospital, Parkville, Australia.
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