Copper toxicity, Wilson’s disease (ATP7B-related)

Gene: ATP7B

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease. Both parents of an affected animal must be carriers of at least one copy of the mutation. Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Substitution, ATP7B gene; c.4151 G>A, p.(R1384Q)

Medical system: Digestive

Breeds: Labrador Retriever

Age of onset of symptoms: 2.5 to 7.5 years

Copper is an essential trace element that is required in several key metabolic body processes. Copper excess and accumulation in the body leads to copper toxicosis which can have both genetic and environmental causes. The genetic disease, seen in both humans and the dog, has historically been called Wilson’s disease, and can involve deregulated copper uptake, utilization and/or excretion by the body.

Hereditary copper toxicosis has been described in the adult Labrador Retriever dog. Clinical signs of affected animals include gastrointestinal stress, anorexia, vomiting and possible jaundice. Hepatitis and eventual cirrhosis can be noted. Laboratory and histological testing indicate excess copper accumulation in liver cells, allowing a diagnosis of copper toxicosis to be made. The disease is observed more often in female animals than in male. More recently, molecular screening studies in 235 Labrador Retrievers identified a mutation within the ATP7B gene as being correlated with increased liver copper concentrations, while a mutation in the ATP7A gene was correlated with reduced liver copper concentrations. Disease status of these animals was not stated. The ATP7B gene codes for a copper transporter protein involved in the excretion of copper in the bile, while the ATP7A gene codes for a copper transporter protein involved in dietary input of copper. A balance between ATP7B and ATP7A gene expression is required for proper copper balance in the body. Mutations within the ATP7B are a known cause of copper toxicity or Wilson’s disease in humans. The ATP7B mutation seen in the Labrador Retriever was subsequently shown to contribute to the copper toxicity seen in Bedlington Terriers, as a modifying factor to the COMMD1 gene mutation.

Although the ATP7B mutation was shown to be correlated with liver copper levels in the Labrador Retriever, it was not shown to be causative for copper toxicity in this breed. Frequencies of the mutation in the Labrador Retriever breed have not been presented. The female bias of the disease in the Labrador Retriever has not been explained. The genetic cause of copper toxicity within a given dog breed is likely to be breed specific. Wilson’s disease in the dog, as in humans, remains a complex polygenic disease that can be affected by environmental factors. Indeed, dietary copper intake is believed to be as important as genetic factors for the incidence of copper toxicity in the dog.