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Abstract

The Long-Evans Cinnamon (LEC) rat shows similarity to Wilson disease in many clinical and biochemical features. We have cloned cDNAs for the rat gene (Atp7b) homologous to the human Wilson disease gene (ATP7B) and have used them to identify a partial deletion in the Atp7b gene in the LEC rat. The deletion removes at least 900 bp of the coding region at the 3' end, includes the crucial ATP binding domain and extends downstream of the gene. Our results provide convincing evidence for defining the LEC rat as an animal model for Wilson disease. This model will be important for studying liver pathophysiology, for developing therapy for Wilson disease and for studying the pathway of copper transport and its possible interaction with other heavy metals.

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The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.

P C BULL, G R Thomas, J M Rommens … (1993)

Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. The gene (WD) has been mapped to chromosome 13 q14.3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease. We show that this sequence forms part of a P-type ATPase gene (referred to here as Wc1) that is very similar to MNK, with six putative metal binding regions similar to those found in prokaryotic heavy metal transporters. The gene, expressed in liver and kidney, lies within a 300 kb region likely to include the WD locus. Two WD patients were found to be homozygous for a seven base deletion within the coding region of Wc1. Wc1 is proposed as the gene for WD.

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The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.

J Pellequer, K Petrukhin, W Wasco … (1993)

Wilson disease (WD) is an autosomal recessive disorder characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain. As shown in the accompanying paper, linkage disequilibrium & haplotype analysis confirmed the disease locus to a single marker interval at 13q14.3. Here we describe a partial cDNA clone (pWD) which maps to this region and shows a particular 76% amino acid homology to the Menkes disease gene, Mc1. The predicted functional properties of the pWD gene together with its strong homology to Mc1, genetic mapping data and identification of four independent disease-specific mutations, provide convincing evidence that pWD is the Wilson disease gene.

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Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.

J Gitschier, Daniel B. Levinson, S Packman … (1992)

Menkes disease is an X-linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood. We have isolated a candidate gene (Mc1) for Menkes disease and find qualitative or quantitative abnormalities in the mRNA in sixteen of twenty-one Menkes patients. Four patients lacking Mc1RNA showed rearrangements of the Menkes gene. The gene codes for a 1,500 amino acid protein, predicted to be a P-type cation-transporting ATPase. The gene product is most similar to a bacterial copper-transporting ATPase and additionally contains six putative metal-binding motifs at the N-terminus. The gene is transcribed in all cell types tested except liver, consistent with the expression of the Menkes defect.

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PubMed ID:: 7951327

DOI:: 10.1038/ng0894-541

ScienceOpen disciplines: Chemistry

Keywords: Adenosine Triphosphatases,genetics,Amino Acid Sequence,Animals,Base Sequence,Cation Transport Proteins,Copper,metabolism,DNA Primers,DNA, Complementary,Disease Models, Animal,Gene Deletion,Hepatolenticular Degeneration,Humans,Mice,Molecular Sequence Data,Rats,Rats, Mutant Strains

The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene.

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Most cited references 16

The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.

The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.

Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.

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