Introduction

The Animal Health Trust is a charity that has been helping dogs, cats and horses for more than half a century. We provide specialist veterinary clinical, diagnostic and surgical services and our successes in research have ranged from major breakthroughs in anaesthesia and surgical techniques to the development of vaccines against diseases such as canine distemper and equine influenza. Our scientists and veterinarians, many of whom are world leaders in their field, work alongside bringing together a wide range of expertise for a co-ordinated attack on animal diseases and injuries. By publishing scientific papers, speaking at conferences and talking to other veterinary surgeons about the cases dealt with, this knowledge is passed on to benefit the maximum number of animals. The canine genetics group is a small team of skilled personnel that liases with clinicians, other scientists within and outside the Trust and dog owners and breeders alike. This unique partnership is what makes the AHT’s research and DNA Diagnostic Service so successful. The genetics group strives to understand the genetic basis of inherited canine disease. The long-term goal of the work we undertake is to identify the genetic mutations that cause inherited disease and develop DNA tests that identify those dogs which carry these causal mutations. Breeders can use the information gleaned from these tests to instigate appropriate breeding programmes that avoid the production of affected dogs and aide in the eventual elimination of inherited disease from breeds at risk.

Basic Genetics

Selective breeding for desirable phenotypic and behavioural traits has produced more than 300 distinct breeds of domestic dog worldwide with each breed being defined by a narrow set of specific physical and behavioural characteristics. Not surprisingly, because many of these key features are maintained by crossing closely related individuals, inherited diseases are very common among purebred dogs. Inherited diseases are caused by mistakes (mutations) within the DNA of genes.

Chromosomes

 Each dog has 38 pairs of ‘autosomes’ and a single pair of ‘sex chromosomes’ in nearly every cell within its body. The autosomes are the same in males and females whereas females have 2 ‘X’ sex chromosomes and males have an ‘X’ and a ‘Y’ chromosome. One of each pair of chromosomes is inherited from the dog’s mother and the other from its father.

DNA & Genes

The chromosomes are made up of deoxyribonucleic acid or DNA. DNA is a long, double stranded, very complex molecule composed of 4 different building blocks or nucleotides (abbreviated to C, G, T and A). It is divided into ‘genes’; every gene is literally a written instruction that codes for the production of a single protein. There are probably about 30 – 40,000 different genes within the DNA of every dog. The dog has 2 copies (or alleles) of each gene, one on the chromosome it inherited from its mother and one on its paternal chromosome. The proteins that are coded for by these genes interact with one another in very specific ways within the body to perform all the functions necessary for life. The order of As, Gs, Cs and Ts within a gene needs to be exactly right for the cells to make the correct proteins; ‘misprints’ or mutations within genes can lead to ‘faulty’ or non-functional proteins and these, in turn, can give rise to disease.

Inherited Disease in the Staffordshire Bull Terrier

As with other breeds of dog the Staffordshire bull terrier suffers from its fair share of inherited disease. The AHT has been researching the genetic basis of two such diseases over the last few years, Hereditary Cataract (HC) and L-2-Hydroxyglutaric Aciduria (L-2-HGA) and is pleased to announce the development of DNA Diagnostic Tests for both these conditions are now available at the AHT.

L-2-Hydroxyglutaric aciduria L-2-HGA (L-2-hydroxyglutaric aciduria) in Staffordshire Bull Terriers is a neurometabolic disorder characterised by elevated levels of L-2-hydroxyglutaric acid in urine, plasma and cerebrospinal fluid. L-2-hydroxyglutarate is normally metabolised to a-ketoglutarate but in affected dogs it is not, and builds up in the body with devastating results. L-2-HGA affects the central nervous system, with clinical signs usually apparent between 6 months and one year (although they can appear later). Symptoms include epileptic seizures, "wobbly" gait, tremors, muscle stiffness as a result of exercise or excitement and altered behavior.

Hereditary Cataract Hereditary cataract in the Staffordshire bull terrier was first reported in the United Kingdom in 1976. The condition is not congenital, so puppies are born with normal eyes, but cataracts begin to appear at a few weeks to months in age, progressing to total cataracts by 2 to 3 years of age. This cataract is always bilateral, symmetrical in the two eyes, and progressive until total with resultant blindness.

Autosomal Recessive Disease

Both HC and L-2-HGA are autosomal recessive conditions. This type of disease is caused by a mutation within a single gene located on one of the 38 pairs of autosomes. Mutations causing recessive diseases can be small (for example a single incorrect nucleotide, or the insertion or deletion of a small number of nucleotides) or large (such as the deletion of a large number of nucleotides). Because the mutations are within genes located on the autosomes both males and females suffer from the disease with equal frequency. A dog has to have a mutation in each copy of the gene (i.e. the copy on each of its chromosomes) before it will actually develop symptoms of the disease. This is known as being homozygous for the disease allele. If it has one mutated copy of the gene and one normal copy it will be a carrier of the disease but will never actually develop symptoms. It can, however, pass the mutation onto future generations. For a dog to be affected with an autosomal recessive disease, both its parents have to be either carriers or affected. If two carriers are mated together on average one in four of their offspring will be affected, one in four will be genetically clear and half will be carriers.

DNA Diagnostic Tests

After several years of research into the genetic basis of these two inherited conditions the AHT is pleased to announce the identification of the mutations that cause both diseases. The research was made possible by funding from the Kennel Club Health Foundation Fund, the American Kennel Club Canine Health Foundation, the Staffordshire Bull Terrier Breed Council and PetSavers. DNA samples from affected dogs and their close relatives were donated by Staffordshire Bull terrier owners and breeders and the AHT is sincerely grateful to all those who donated samples from their dogs.

How Breeders Can Benefit From the DNA Diagnostic Tests

Owners can now submit a DNA sample from any dog for testing and find out whether the dog is clear, a carrier or affected with either, or both, HC and L-2-HGA. The owner will receive a certificate that states whether the dog is Clear, Carrier or Affected, with the following explanations:

The Way Forward

Now that genetic tests are available for both HC and L-2-HGA it is possible to avoid breeding any more dogs that are affected with either of these conditions. Initial L-2-HGA test results indicate that approximately 15% of dogs tested are carriers of the L-2-HGA mutation and it is likely that a similar proportion of dogs will also carry the HC mutation. Some dogs will carry both mutations but as many as 20-25% of Staffordshire bull terriers could carry at least one mutation. Therefore, geneticists at the AHT advise against eliminating carriers from the breeding population because doing so will result in an unacceptable reduction in the gene pool that can never be recovered. Instead, our advice would be to test all dogs that might be used for breeding, and if a dog is identified as being a carrier of either HC or L-2-HGA they should only be mated to dogs that have tested clear and any resulting puppies that may be used for breeding should also be tested. This practice will allow gradual elimination of the mutations from the breeding population, while also allowing those desirable characteristics exhibited by the carriers to be passed to future generations. As long as carriers are always bred to clear dogs no affected puppies will be produced and although some carriers will be bred they will be perfectly healthy with respect to both these diseases. Below is a list of various combinations of dogs, their expected outcomes, and whether they are recommended: