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Canine models of copper toxicosis for understanding mammalian copper metabolism.

Fieten H, Leegwater PA, Watson AL, Rothuizen J - Mamm. Genome (2011)

Bottom Line: In man, Wilson's disease is the best studied disorder of copper overload, resulting from mutations in the gene coding for the copper transporter ATP7B.Although advances have been made in unraveling the genetic background of disorders of copper metabolism in man, many questions regarding disease mechanisms and copper homeostasis remain unanswered.Unlike the heterogeneity of most human populations, the genetic structure within a purebred dog population is homogeneous, which is advantageous for unraveling the molecular genetics of complex diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3584 CM Utrecht, The Netherlands. H.Fieten@uu.nl

ABSTRACT
Hereditary forms of copper toxicosis exist in man and dogs. In man, Wilson's disease is the best studied disorder of copper overload, resulting from mutations in the gene coding for the copper transporter ATP7B. Forms of copper toxicosis for which no causal gene is known yet are recognized as well, often in young children. Although advances have been made in unraveling the genetic background of disorders of copper metabolism in man, many questions regarding disease mechanisms and copper homeostasis remain unanswered. Genetic studies in the Bedlington terrier, a dog breed affected with copper toxicosis, identified COMMD1, a gene that was previously unknown to be involved in copper metabolism. Besides the Bedlington terrier, a number of other dog breeds suffer from hereditary copper toxicosis and show similar phenotypes to humans with copper storage disorders. Unlike the heterogeneity of most human populations, the genetic structure within a purebred dog population is homogeneous, which is advantageous for unraveling the molecular genetics of complex diseases. This article reviews the work that has been done on the Bedlington terrier, summarizes what was learned from studies into COMMD1 function, describes hereditary copper toxicosis phenotypes in other dog breeds, and discusses the opportunities for genome-wide association studies on copper toxicosis in the dog to contribute to the understanding of mammalian copper metabolism and copper metabolism disorders in man.

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Related in: MedlinePlus

Model of hepatocyte copper metabolism. Copper (diamonds) enters the cell via copper transporter 1 (CTR1) and is sequestered in the cytoplasm by the small molecules metallothionein (MT) and glutathione (GSH). Shuttling of copper to the destination molecules takes place via copper chaperones. COX17 shuttles copper to the cytochrome C oxidase (CcO) in the mitochondria. CCS is the chaperone for superoxide dismutase (SOD1). Recently, COMMD1 was shown to interact with SOD1 and this interaction requires CCS-mediated copper incorporation in SOD1. ATOX1 transports copper to ATP7B in the trans-Golgi network, where incorporation of copper in apo-ceruloplasmin (CP) takes place. Holo-ceruloplasmin is subsequently excreted in the plasma. The precise mechanism for export of excess copper in the bile is not completely resolved, but it is hypothesized that ATP7B and COMMD1 mediate fusion of copper-loaded vesicular compartments to the apical membrane. Furthermore, COMMD1 may play a role in the maintenance of ATP7B. XIAP can inhibit COMMD1 by promoting its degradation, resulting in cellular copper accumulation. XIAP itself can receive copper from CCS, and copper binding of XIAP results in its degradation and decrease in caspase inhibition, which may result in enhanced apoptosis
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Fig1: Model of hepatocyte copper metabolism. Copper (diamonds) enters the cell via copper transporter 1 (CTR1) and is sequestered in the cytoplasm by the small molecules metallothionein (MT) and glutathione (GSH). Shuttling of copper to the destination molecules takes place via copper chaperones. COX17 shuttles copper to the cytochrome C oxidase (CcO) in the mitochondria. CCS is the chaperone for superoxide dismutase (SOD1). Recently, COMMD1 was shown to interact with SOD1 and this interaction requires CCS-mediated copper incorporation in SOD1. ATOX1 transports copper to ATP7B in the trans-Golgi network, where incorporation of copper in apo-ceruloplasmin (CP) takes place. Holo-ceruloplasmin is subsequently excreted in the plasma. The precise mechanism for export of excess copper in the bile is not completely resolved, but it is hypothesized that ATP7B and COMMD1 mediate fusion of copper-loaded vesicular compartments to the apical membrane. Furthermore, COMMD1 may play a role in the maintenance of ATP7B. XIAP can inhibit COMMD1 by promoting its degradation, resulting in cellular copper accumulation. XIAP itself can receive copper from CCS, and copper binding of XIAP results in its degradation and decrease in caspase inhibition, which may result in enhanced apoptosis

Mentions: The copper chaperone ATOX1 (Klomp et al. 1997) delivers copper to ATP7B that is located in the trans-Golgi compartment (Hamza et al. 1999; Larin et al. 1999; van Dongen et al. 2004). Here, copper is necessary for the formation of holo-ceruloplasmin, which is subsequently secreted into the blood (Yanagimoto et al. 2011). In addition, ATP7B facilitates the excretion of excess copper into the bile (Cater et al. 2006) (Fig. 1).Fig. 1


Canine models of copper toxicosis for understanding mammalian copper metabolism.

Fieten H, Leegwater PA, Watson AL, Rothuizen J - Mamm. Genome (2011)

Model of hepatocyte copper metabolism. Copper (diamonds) enters the cell via copper transporter 1 (CTR1) and is sequestered in the cytoplasm by the small molecules metallothionein (MT) and glutathione (GSH). Shuttling of copper to the destination molecules takes place via copper chaperones. COX17 shuttles copper to the cytochrome C oxidase (CcO) in the mitochondria. CCS is the chaperone for superoxide dismutase (SOD1). Recently, COMMD1 was shown to interact with SOD1 and this interaction requires CCS-mediated copper incorporation in SOD1. ATOX1 transports copper to ATP7B in the trans-Golgi network, where incorporation of copper in apo-ceruloplasmin (CP) takes place. Holo-ceruloplasmin is subsequently excreted in the plasma. The precise mechanism for export of excess copper in the bile is not completely resolved, but it is hypothesized that ATP7B and COMMD1 mediate fusion of copper-loaded vesicular compartments to the apical membrane. Furthermore, COMMD1 may play a role in the maintenance of ATP7B. XIAP can inhibit COMMD1 by promoting its degradation, resulting in cellular copper accumulation. XIAP itself can receive copper from CCS, and copper binding of XIAP results in its degradation and decrease in caspase inhibition, which may result in enhanced apoptosis
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3275736&req=5

Fig1: Model of hepatocyte copper metabolism. Copper (diamonds) enters the cell via copper transporter 1 (CTR1) and is sequestered in the cytoplasm by the small molecules metallothionein (MT) and glutathione (GSH). Shuttling of copper to the destination molecules takes place via copper chaperones. COX17 shuttles copper to the cytochrome C oxidase (CcO) in the mitochondria. CCS is the chaperone for superoxide dismutase (SOD1). Recently, COMMD1 was shown to interact with SOD1 and this interaction requires CCS-mediated copper incorporation in SOD1. ATOX1 transports copper to ATP7B in the trans-Golgi network, where incorporation of copper in apo-ceruloplasmin (CP) takes place. Holo-ceruloplasmin is subsequently excreted in the plasma. The precise mechanism for export of excess copper in the bile is not completely resolved, but it is hypothesized that ATP7B and COMMD1 mediate fusion of copper-loaded vesicular compartments to the apical membrane. Furthermore, COMMD1 may play a role in the maintenance of ATP7B. XIAP can inhibit COMMD1 by promoting its degradation, resulting in cellular copper accumulation. XIAP itself can receive copper from CCS, and copper binding of XIAP results in its degradation and decrease in caspase inhibition, which may result in enhanced apoptosis
Mentions: The copper chaperone ATOX1 (Klomp et al. 1997) delivers copper to ATP7B that is located in the trans-Golgi compartment (Hamza et al. 1999; Larin et al. 1999; van Dongen et al. 2004). Here, copper is necessary for the formation of holo-ceruloplasmin, which is subsequently secreted into the blood (Yanagimoto et al. 2011). In addition, ATP7B facilitates the excretion of excess copper into the bile (Cater et al. 2006) (Fig. 1).Fig. 1

Bottom Line: In man, Wilson's disease is the best studied disorder of copper overload, resulting from mutations in the gene coding for the copper transporter ATP7B.Although advances have been made in unraveling the genetic background of disorders of copper metabolism in man, many questions regarding disease mechanisms and copper homeostasis remain unanswered.Unlike the heterogeneity of most human populations, the genetic structure within a purebred dog population is homogeneous, which is advantageous for unraveling the molecular genetics of complex diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3584 CM Utrecht, The Netherlands. H.Fieten@uu.nl

ABSTRACT
Hereditary forms of copper toxicosis exist in man and dogs. In man, Wilson's disease is the best studied disorder of copper overload, resulting from mutations in the gene coding for the copper transporter ATP7B. Forms of copper toxicosis for which no causal gene is known yet are recognized as well, often in young children. Although advances have been made in unraveling the genetic background of disorders of copper metabolism in man, many questions regarding disease mechanisms and copper homeostasis remain unanswered. Genetic studies in the Bedlington terrier, a dog breed affected with copper toxicosis, identified COMMD1, a gene that was previously unknown to be involved in copper metabolism. Besides the Bedlington terrier, a number of other dog breeds suffer from hereditary copper toxicosis and show similar phenotypes to humans with copper storage disorders. Unlike the heterogeneity of most human populations, the genetic structure within a purebred dog population is homogeneous, which is advantageous for unraveling the molecular genetics of complex diseases. This article reviews the work that has been done on the Bedlington terrier, summarizes what was learned from studies into COMMD1 function, describes hereditary copper toxicosis phenotypes in other dog breeds, and discusses the opportunities for genome-wide association studies on copper toxicosis in the dog to contribute to the understanding of mammalian copper metabolism and copper metabolism disorders in man.

Show MeSH
Related in: MedlinePlus