Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients

Abstract

Wilson disease is a human disorder of copper metabolism resulting in toxic copper accumulation. Patients present with a high clinical variability, even when sharing identical mutations. MURR1, the gene causing canine copper toxicosis in Bedlington terriers, maps to chromosome 2 in humans, a region different to the Wilson gene locus. MURR1 might influence human copper metabolism and the clinical presentation of Wilson disease patients. This study analyzed MURR1 gene sequence in Wilson disease patients and MURR1 gene transcription in selected patients. Mutation analysis of three exons of the MURR1 gene including the intron-exon boundaries was performed in 63 Wilson disease patients by direct sequencing. Of the 63 Wilson patients 19 (30%) had basepair changes in the MURR1 gene. Three intronic base pair changes, one new sequence variation and two known polymorphisms were detected, including the GAT/GAC heterozygous state at codon Asn 164 in 15 (24%) of the analyzed patients. This suggests that GAT/GAC heterozygous state at codon Asn 164 is associated with an earlier onset of disease.

The canine genome

“…Contrary to expectation, this disease did not map to the portion of the canine genome analogous to the Wilson's disease locus in humans (Yuzbasiyan-Gurkan et al 1997;van de Sluis et al 1999). Analysis of the human homolog of MURR1 in Wilson's disease patients has subsequently proven provocative, as those who carry particular sequence variants appear to present with earlier onset disease (Stuehler et al 2004), suggesting that the two genes or their products interact to accelerate disease.…”

COMMD1 (Copper Metabolism MURR1 Domain-containing Protein 1) Regulates Cullin RING Ligases by Preventing CAND1 (Cullin-associated Nedd8-dissociated Protein 1) Binding

“…A large deletion in the canine COMMD1 gene, which abolishes protein expression, leads to pathologic copper accumulation, cirrhosis, and liver failure in Bedlington terriers (17). Although humans with pathologic copper accumulation caused by COMMD1 mutations have not been identified (22,23), a role for this gene in modulating the phenotype of Wilson's disease has been proposed (24). Moreover, COMMD1 has been found to have copper binding activity in vitro (25) and can modulate the matura-tion of the copper-containing enzyme SOD1 (26).…”

A Novel Mutation in ATP7B Gene Associated with Severe Neurological and Psychiatric Symptoms

“…cantly infl uence both the time of onset and the mode of presentation, for example the apoE genotype [9] or the MURR1 gene [10] , we suggest that in our case the novel detected mutation D1279Y contributes to the severe neurological and psychiatric symptoms. The later onset may be attributed to the presence of H1069Q.…”