Canine models of copper toxicosis for understanding mammalian copper metabolism

Fieten, Hille; Leegwater, P.A.J.; Watson, Adrian; Rothuizen, J.

doi:10.1007/s00335-011-9378-7

Cited by 45 publications

(42 citation statements)

References 134 publications

(174 reference statements)

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“…Among them the most significant are: mitochondrial respiration, antioxidative activity, synthesis of neurotransmitters, formation of connective tissue, participation in the production of tissue pigment and the key action in the iron metabolism [1,2]. Copper also takes part in the metabolism of glucose and lipids, myelin formation, osteogenesis as well as in the development of common integument keratine formations [1].…”

Section: Introductionmentioning

confidence: 99%

“…Despite its indispensability, high copper tissue concentration shows a toxic effect on the organism. Thus the distribution of that element is subject to close regulation [1,2]. Although a great interest is taken in the process of understanding the mechanisms of the ion balance disturbance, they are still unclear [4].…”

Section: Introductionmentioning

confidence: 99%

“…Copper toxicosis in some dog breeds arouses interest of many scientists due to its specific pathogenesis and numerous similarities to the storage diseases observed in human beings, such as Wilson's disease [2,5]. Up till now the hereditary copper toxicosis has been diagnosed, among others, in Bedlington terriers, Skye terriers, West highland white terriers, Dalmatians, Dobermanns and Retrievers [2,[5][6][7][8][9][10]. Genetic studies in the Bedlington terriers identified COMMD1 gene which plays an important role in copper metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…In this breed copper levels are not as high as in case of Bedlington terriers. Most of affected dogs has copper concentrations around 2,000 µg g -1 dwl and the highest level reported was 6,800 µg g -1 dwl [2,5,6]. The problem of element accumulation in the tissues of dogs of other breeds and crossbreeds has not been fully studied yet.…”

Section: Introductionmentioning

confidence: 99%

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Dependence between Cu concentration in the liver, kidneys and skeletal muscles of canine females

2012

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Abstract:The aim of the investigations was the determination of the Cu contents in the liver, kidneys and skeletal muscles of canine females.Material for research was collected post mortem from 45 animals aged 1 to 18 years coming from the Warsaw area. The effect of the health state, age and life conditions on the distribution of copper in the investigated organs was estimated. That element was determined using the method of inductively coupled plasma-atomic emission spectrometry (ICP-AES). In the liver, the average Cu contents amounted to 24.04 mg kg -1 wet weight, in kidneys to 2.90 mg kg -1 wet weight and in muscles to 0.94 mg kg -1 wet weight. The highest values of copper content in particular tissues and organs were noted in the group of animals with neoplastic changes. In respect to the animal age the highest mean values of the copper content were noted in the oldest animals. They amounted to 30.97 mg kg -1 in the liver, 3.34 mg kg -1 in kidneys and 1.18 mg kg -1 wet weight in muscles. Considering life conditions of the dogs it was observed that the higher mean values in all the investigated organs occurred in dogs coming from the urban areas.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dependence between Cu concentration in the liver, kidneys and skeletal muscles of canine females

2012

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“…Fieten et al [63] summarised that genetic studies into canine Cu toxicosis, especially the findings in the Bedlington terriers and hereditary Cu toxicosis phenotypes in other dog breeds, will contribute to an increased knowledge into mammalian Cu metabolism and human Cu storage diseases. Furthermore, the authors underlined the benefit of the genetic homogeneity within a purebred dog population which is advantageous for unraveling the molecular genetics of complex diseases using the dog as an animal model [63].…”

Section: Copper Metabolism In Animals -Usage As An Animal Modelmentioning

confidence: 99%

Selenium, copper and iron in veterinary medicine—From clinical implications to scientific models

Humann-Ziehank

2016

Journal of Trace Elements in Medicine and Biology

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Molecular Genetics of Wilson Disease

Roberts

2013

Encyclopedia of Life Sciences

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Wilson disease is an autosomal‐recessive genetic disorder of hepatocellular copper disposition. It is rare but has a worldwide distribution. It is clinically diverse. Disease patterns include various kinds of liver disease; neurological movement disorders and psychiatric disease including psychosis, and less commonly recurrent haemolytic anaemia, osseomuscular abnormalities and cardiac dysrhythmias. The classic eye finding, the Kayser–Fleischer ring, has no functional impact. Thus far, only one gene has been identified whose mutations are causal for Wilson disease, ATP7B on chromosome 13q14.3, cloned in 1993. More than 500 mutations have been identified. The encoded protein is a metal‐transporting P‐type adenosine triphosphatase (ATPase), the Wilson ATPase, similar to copper transporters across the phyla. Simple genotypic explanation for the phenotypic diversity does not exist. The important genotype–phenotype correlation is that if the Wilson ATPase is absent or nonfunctional, severe disease (usually hepatic) commonly develops in the first decade of life. Clinically evident Wilson disease is fatal if not treated. The broad age range of diagnoses (3–80+ years) raises the question of incomplete penetrance, an issue along with gene modifiers currently under investigation. The possibility that mutations in other genes may result in Wilson disease has not been entirely eliminated. The contribution of ATP7B to non‐Wilsonian diseases is being determined. Key Concepts: Wilson disease is a rare (30 per million population, on average) autosomal‐recessive disorder of hepatic copper disposition. Wilson disease can present as almost any form of hepatic disease, or as neurological movement disorders, or as psychiatric disease. Genetic diagnosis is definitive; clinical application of genetic findings requires skilled interpretation; success rate for identifying one or both mutations can be highly variable. Most affected individuals are compound heterozygotes. Genetic testing is most efficient for investigating first‐degree relatives, who must be assessed for Wilson disease once a single family member has been diagnosed with Wilson disease. Wilson disease is an example of ‘endogenous hepatotoxicity’ where a normal component of the functioning organism is mishandled and becomes toxic. The mechanism of liver (and likely brain) damage involves oxidative stress with damage to mitochondria; apoptosis is typical. Concepts relating to drug‐induced hepatotoxicity are highly relevant to understanding the mechanism of damage and devising treatments. Metalloproteomics is a research strategy for examining copper disposition in normal and abnormal models/organisms. More than 500 mutations in ATP7B have been identified. These are mainly missense mutations, and less frequently small deletions or insertions, nonsense or splice‐site mutations. In contrast, the homologous gene ATP7A , abnormal in the X‐linked recessive disorder Menkes disease (with copper insufficiency), displays mainly large deletions. Predictably, the phenotypic variation depends on complex factors besides the genotype. The only important genotype–phenotype correlation is that severe disease (usually hepatic) typically develops very early in life if the Wilson ATPase is absent or nonfunctional. A convincing example of this correlation is provided by comparison of the Atp7b ‐knockout mouse and the toxic milk (tx‐j) mouse, which has a point mutation. Few modifying genes have been identified. Candidates include apolipoprotein E, human prion gene and BIRC4/XIAP. Females seem to have more severe Wilson disease. Other disorders of copper disposition exist. These include defects in ceruloplasmin production (aceruloplasminaemia and AT‐1 defect), various congenital glycosylation disorders, Indian childhood cirrhosis and its variants. In the Bedlington terrier, hepatic copper toxicosis is usually related to mutations in the gene for COMMD1. ATP7B may play a secondary role in some forms of Alzheimer disease. The Wilson ATPase plays a direct role in the hepatocellular handling of platinum compounds such as cisplatin.

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Canine models of copper toxicosis for understanding mammalian copper metabolism

Cited by 45 publications

References 134 publications

Dependence between Cu concentration in the liver, kidneys and skeletal muscles of canine females

Dependence between Cu concentration in the liver, kidneys and skeletal muscles of canine females

Selenium, copper and iron in veterinary medicine—From clinical implications to scientific models

Molecular Genetics of Wilson Disease

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