Abstract
Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted.
Highlights
The essential micronutrient copper plays a key role in several vital biological processes including neurotransmitter synthesis, antioxidant defense, mitochondrial respiration, iron metabolism, pigmentation, and connective tissue formation [1,2,3,4,5,6,7]
The etiology of copper toxicosis in Labrador retrievers is multifactorial, a genome wide association study showed a clear association of hepatic copper levels with variations in the Wilson disease gene ATP7B
Illustrated by the examples of the identification of COMMD1 in the Bedlington terriers and ATP7A and ATP7B in the Labrador retrievers, gene mapping studies in pure bred dog populations affected with copper toxicosis are a powerful tool to identify genes involved in copper metabolism
Summary
The essential micronutrient copper plays a key role in several vital biological processes including neurotransmitter synthesis, antioxidant defense, mitochondrial respiration, iron metabolism, pigmentation, and connective tissue formation [1,2,3,4,5,6,7]. The body size of dogs is more in the range of that of humans and facilitates translation of procedures (including those needed for application of stem-cell treatments such as catheterization of the vena porta for intraportal delivery of cell-transplants to the liver) and collection of multiple liver biopsies over time from the same animal. Their long lifespan (up to 16 years) facilitates the evaluation of long-term treatment effects. We will discuss the present canine models of copper metabolism, and the role of the canine models in identification of new genes, the opportunities for development of new medical and dietary treatments, and the possibility of auto-transplantation of gene-corrected organoids in dogs as a large animal model for copper storage diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
