<i>COMMD1 (MURR1)</i> as a candidate in patients with copper storage disease of undefined etiology

Coronado, VA; Bonneville, JA; Nazer, Hisham M.; Roberts, E. A.; Dw, Cox

doi:10.1111/j.1399-0004.2005.00524.x

Cited by 36 publications

(14 citation statements)

References 14 publications

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“…There may be additional genes involved in copper storage, but none have been identified yet. MURR1/COMMD1, proposed as the gene involved in Bedlington copper toxicosis, is unlikely to contribute to copper storage disease in humans [21,22]. In one recently published cohort study of 163 patients with a mean follow-up of 17 years in an experienced European centre, up to 15% of patients with established diagnosis of WD had no detectable genetic mutations, and only slightly over half had mutations identified on both chromosomes based on sequencing of exon 3-17 of the ATP7B gene [16].…”

Section: Discussionmentioning

confidence: 99%

Three atypical cases of Wilson disease: Assessment of the Leipzig scoring system in making a diagnosis

Xuan¹,

Bookman²,

Cox³

et al. 2007

Journal of Hepatology

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Section: Discussionmentioning

confidence: 99%

Three atypical cases of Wilson disease: Assessment of the Leipzig scoring system in making a diagnosis

Xuan¹,

Bookman²,

Cox³

et al. 2007

Journal of Hepatology

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“…In contrast to WD, Bedlington terriers affected with CT do not display any signs of neurological defects and have normal serum concentrations of the copper-bound ferroxidase ceruloplasmin (Cp) [10]. Although COMMD1 has been suggested as a candidate gene for the non-Wilsonian copper storage disorders ICC, ETIC and ICT, no mutations in COMMD1 have been identified in these patients so far [11], [12].…”

Section: Introductionmentioning

confidence: 99%

Liver-Specific Commd1 Knockout Mice Are Susceptible to Hepatic Copper Accumulation

et al. 2011

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Canine copper toxicosis is an autosomal recessive disorder characterized by hepatic copper accumulation resulting in liver fibrosis and eventually cirrhosis. We have identified COMMD1 as the gene underlying copper toxicosis in Bedlington terriers. Although recent studies suggest that COMMD1 regulates hepatic copper export via an interaction with the Wilson disease protein ATP7B, its importance in hepatic copper homeostasis is ill-defined. In this study, we aimed to assess the effect of Commd1 deficiency on hepatic copper metabolism in mice. Liver-specific Commd1 knockout mice (Commd1 Δhep) were generated and fed either a standard or a copper-enriched diet. Copper homeostasis and liver function were determined in Commd1 Δhep mice by biochemical and histological analyses, and compared to wild-type littermates. Commd1 Δhep mice were viable and did not develop an overt phenotype. At six weeks, the liver copper contents was increased up to a 3-fold upon Commd1 deficiency, but declined with age to concentrations similar to those seen in controls. Interestingly, Commd1 Δhep mice fed a copper-enriched diet progressively accumulated copper in the liver up to a 20-fold increase compared to controls. These copper levels did not result in significant induction of the copper-responsive genes metallothionein I and II, neither was there evidence of biochemical liver injury nor overt liver pathology. The biosynthesis of ceruloplasmin was clearly augmented with age in Commd1 Δhep mice. Although COMMD1 expression is associated with changes in ATP7B protein stability, no clear correlation between Atp7b levels and copper accumulation in Commd1 Δhep mice could be detected. Despite the absence of hepatocellular toxicity in Commd1 Δhep mice, the changes in liver copper displayed several parallels with copper toxicosis in Bedlington terriers. Thus, these results provide the first genetic evidence for COMMD1 to play an essential role in hepatic copper homeostasis and present a valuable mouse model for further understanding of the molecular mechanisms underlying hepatic copper homeostasis.

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“…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).…”

mentioning

confidence: 99%

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

Mao¹,

Gluck

Chen³

et al. 2011

Journal of Biological Chemistry

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Cullin RING ligases (CRLs), the most prolific class of ubiquitin ligase enzymes, are multimeric complexes that regulate a wide range of cellular processes. CRL activity is regulated by CAND1 (Cullin-associated Nedd8-dissociated protein 1), an inhibitor that promotes the dissociation of substrate receptor components from the CRL. We demonstrate here that COMMD1 (copper metabolism MURR1 domain-containing 1), a factor previously found to promote ubiquitination of various substrates, regulates CRL activation by antagonizing CAND1 binding. We show that COMMD1 interacts with multiple Cullins, that the COMMD1-Cul2 complex cannot bind CAND1, and that, conversely, COMMD1 can actively displace CAND1 from CRLs. These findings highlight a novel mechanism of CRL activation and suggest that CRL regulation may underlie the pleiotropic activities of COMMD1.

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COMMD1 (MURR1) as a candidate in patients with copper storage disease of undefined etiology

Cited by 36 publications

References 14 publications

Three atypical cases of Wilson disease: Assessment of the Leipzig scoring system in making a diagnosis

Three atypical cases of Wilson disease: Assessment of the Leipzig scoring system in making a diagnosis

Liver-Specific Commd1 Knockout Mice Are Susceptible to Hepatic Copper Accumulation

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

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