COMMD1 Exemplifies the Power of Inbred Dogs to Dissect Genetic Causes of Rare Copper-Related Disorders.

Abstract

Simple SummaryResearch on rare diseases has specific problems, such as low or small patient groups, limited public awareness, and limited financial support. By definition, a rare disease affects not more than 50 per 100,000 individuals, but with over 6000 unique, rare diseases, more than 300 million people are affected worldwide. Especially, genetic screens are difficult to perform for rare diseases. Due to selective inbreeding in dogs, often these rare diseases present at high frequency in specific dog breeds. This paper in the special issue on “(epi) genetic disorders in companion animals” describes an example of how a novel gene was found that regulates copper accumulation in the liver in a specific dog breed, the Bedlington terriers, and describes an example of how gene products titrate each other’s function on the liver copper accumulation in Labrador retrievers. These two examples clearly show the power in dog genetics for both veterinary and human medicine. Although inbreeding is under great societal scrutiny due to its consequential large number of inherited diseases, dog genetics will directly positively influence animal welfare, in addition to basic knowledge of biochemical regulation systems, and lastly, it will be beneficial for people suffering from rare diseases.Wilson’s Disease is a rare autosomal recessive disorder in humans, often presenting with hepatic copper overload. Finding the genetic cause of a rare disease, especially if it is related to food constituents like the trace element copper, is a Herculean task. This review describes examples of how the unique population structure of in-bred dog strains led to the discovery of a novel gene and two modifier genes involved in inherited copper toxicosis. COMMD1, after the discovery in 2002, was shown to be a highly promiscuous protein involved in copper transport, protein trafficking/degradation, regulation of virus replication, and inflammation. Mutations in the ATP7A and ATP7B proteins in Labrador retrievers and Dobermann dogs resulted in a wide variation in hepatic copper levels in these breeds. To our knowledge, numerous dog breeds with inherited copper toxicosis of unknown genetic origin exist. Therefore, the possibility that men’s best friend will provide new leads in rare copper storage diseases seems realistic.