Introduction

Over the years there has been a shift in the profile of diseases that veterinarians encounter.  Improvements and developments of antibiotics, anthelmintics and more effective vaccines have controlled many of the infectious diseases that caused problems in the past.  As the frequency of these infectious diseases has declined, there has been a relative increase in diseases that have a genetic basis.  This is particularly obvious in companion animals, less so in livestock. 

Types of Inherited disease

Around 400 inherited diseases have been recognised in the dog, making it second only to the human in terms of the number of known inherited diseases attributed to it.  These diseases result from mutation of one or more genes that make up the canine genome, approximately 40,000 genes on present–day estimates.  There are two kinds of gene mutation that can occur: a dominant and a recessive mutation.  In order to understand the difference you have to remember that dogs are diploid, i.e. each cell in the body (with the exception of red blood cells and gametes, i.e. eggs and sperm) has two copies of each and every gene.  If a gene undergoes a dominant mutation then the consequences will be felt even though there will be a perfectly normal, second copy of this gene.   If, on the other hand, the initial mutation is a recessive mutation, its effects will not be felt in the presence of the normal, second copy of the gene.   In other words, you need two copies of the recessively mutated gene before the consequences are felt.  Inherited disease can therefore be categorised into recessive disease and dominant disease, depending on the initial gene mutation that caused the inherited disease.

There is one further sub-division that is determined by the number of different genes that are involved in the inherited disease.  The simplest forms are the so-called single gene disorders, i.e. where the disease results from mutation of just one single gene.  So, you can have simple dominant diseases, where affected individuals have just one copy of the mutant gene, which could have been inherited from either the father or the mother.  You can also have simple recessive diseases where affected individuals have two copies of the recessive mutation, one inherited from the mother and the other from the father.  Individuals that have one recessive mutant gene and one normal version of this gene are termed carriers; such individuals will not be clinically affected by the condition that results from the recessive mutation.  However, a carrier will pass on the recessive mutant gene version to approximately half of its offspring, the remaining 50% receiving the normal version of the gene.

There is one special type of single gene disorder that is worthy of mention, namely when the mutant gene involved is present on the X chromosome, one of the two chromosomes that determine the sex of an individual.  (In mammals, females carry two copies of the X chromosome, whereas males have one X chromosome and one Y chromosome).  Such diseases are commonly referred to as either being sex-linked or X-linked, the more formal of the two descriptions.  X-linked diseases can be either dominant or recessive.  X-linked recessive diseases have a very characteristic pattern of inheritance, as exemplified by the inheritance of haemophilia A, a disease that results from a recessive mutation of the gene for blood clotting Factor VIII protein that resides of the X chromosome.  The disease is characteristically passed down the female line and produces only affected male offspring.  The reason is that females are in fact carriers, and therefore unaffected, clinically: one of their X chromosomes will carry the normal factor VIII gene and the other the mutant factor VIII gene.  Approximately half of their male offspring will inherit the normal X chromosome and the other half the mutant X chromosome.   Those male offspring (XY) inheriting the mutant X from the mother will be clinically affected because the Y chromosome does not possess a normal factor VIII gene that can compensate for the mutant gene on its X chromosome.

The final category of inherited diseases are those that are genetically complex, resulting from mutations in more than one different gene.  This particular category is often referred to as polygenic diseases, reflecting the multiple gene involvement.  Unlike simple dominant and simple recessive disease, where you get quite predictable patterns of inheritance, it is much more difficult to discern precise patterns of inheritance of polygenic diseases across the generations.  Polygenic diseases by their very nature are more complex and therefore difficult to address.  Unfortunately, many of the canine inherited diseases that most exercise our minds are polygenic in nature; diseases like hip and elbow dysplasia, epilepsy, inherited cardiac disease and cancer.

The genetic basis of inherited disease

Genes are genetic blueprints, transmitted from generation to generation, which contain all of the information necessary to produce an individual of a species.  They are, of course, made of deoxyribonucleic acid (DNA).  One of the major discoveries of the 20^th Century was the unravelling of the chemical structure of DNA that gave us an explanation for just how genetic plans are stored.  DNA is essentially a chemical alphabet made up of four bases called adenine (A), thymine (T), guanine (G) and cytosine (C).  The linear sequence of these bases within a gene, often running into thousands of bases, is used to store the information present in that gene. Genes, therefore, represent unique base sequences that spell out the order and identity of the amino acids that make up the proteins of the body.  Each gene contains a plan, a unique base sequence, which is used to assemble a unique protein.  It is the activities of these proteins, working either individually or in co-ordinated groups, which represent the functional expression of the information present in the genes.

A quick overview of the visual transduction pathway in retinal cells will demonstrate how the products of genes, the proteins, work in a highly orchestrated fashion to facilitate vision.   The light energy falling on the retina activates a protein called rhodopsin, one of the major protein components of retinal cells, so that it can now interact with a second protein called transducin.  The results of this interaction is then the activation of a third protein called cyclic GMP phosphodiesterase.  Once activated, this enzyme starts to degrade a small molecule called cyclic GMP which results in the closure of membrane channels that initiates a nerve impulse that passes down the optic nerve to the brain.

Very occasionally, the base sequence within a particular gene is altered by mutation.  Mutations can result from a simple base change, e.g. a C changed to a G (called a point mutation), inserting extra base sequence or deleting part of the base sequence within a gene or the rearrangement of part of a gene’s base sequence.   Obviously, any alteration to the base sequence within a gene has the potential to alter the genetic plan that the gene stores.  Fortunately, many of the genetic mutations that have accumulated in DNA are neutral and have no consequences for the plan embedded in the gene.  In some instances, the mutation might even be beneficial and lead to an improved genetic plan for the gene.  However, in some cases the effect of the mutation can have negative consequences leading to the synthesis of a protein with an altered biological activity, or even the complete loss of a biologically active protein product.   Depending on the function of the protein, the loss /alteration of biological activity as a result of the mutation to its gene could well interfere with a physiological process resulting in a disease state.  If the mutant gene then finds its way it the gametes of the reproductive system (ova or sperm), then the original mutation will give rise to an inherited disease that will pass from generation to generation.

Going back to the visual transduction pathway.  One of the best-characterised inherited diseases in the dog is that known as progressive retinal atrophy (PRA), a condition that is present in a number of different breeds.  Although this condition is clinically similar in different breeds, it is known to have a number of different genetic causes.  The precise mutation has been identified in three different breeds: The Irish setter, Cardigan Welsh corgi and sloughi.  In all three cases, the mutation affects the enzyme cyclic GMP Phosphodiesterase, rendering it inactive.  This means that cyclic GMP slowly builds up in the retinal cells of the affected dog.  Cyclic GMP is cytotoxix and so this slow build up results in the progressive death of retinal cells.

Identifying the genes involved in inherited disease and the development of genetic screening programmes

Those of you who keep half an eye on current scientific affairs will not have failed to notice the publicity surrounding the Human Genome Project.  One of its major milestones was recently achieved when all of the 3,000,000,000 DNA base sequence, that represents the human genome, was elucidated.  The next challenge for the project is to see precisely where in this formidable sequence the 40,000 or so human genes reside and then, finally, to try to discover the function of each of these and to attempt to predict what might happen if one of them is mutated.

Similar, although it has to be added less ambitious, projects have been initiated in other species like cow, sheep, pig, chicken, horse, dog and cat.  One of the goals of these projects is to produce genetic maps of the species’ chromosomes.  Such maps greatly facilitate scientists’ search for particular genes in the genome.  It is now therefore far simpler to identify individual genes in these species, whether they be involved in economic traits, like milk production or fat production, or involved in inherited diseases when mutated.

Identification of the mutations that result in particular inherited diseases can give great insight into the disease.  Knowing the gene might help us better understand the pathology of the disease and help in developing new intervention therapies.  Ultimately, it might be possible to consider gene replacement therapies as a remedy for some of these ills.   Knowing the underlying genetic cause, i.e. the precise mutation, will also allow the development of relatively simple DNA tests for the presence or absence of the mutation in particular individuals.  The availability of such disease specific DNA tests will offer the facility to pre-screen potential breeding stock and determine their genotype with respect to a given inherited disease and then take note of the information when designing breeding programmes.  The availability of DNA tests for mutations responsible for inherited disease will greatly facilitate breeders’ efforts to control the disease prevalence through selective breeding.

Once a particular mutation responsible for an inherited disease has been identified, it is a relatively simple task to develop a DNA test for the presence, or absence, of the mutant gene in the DNA of any individual of the species.  All that is required is a small amount of the individual’s DNA  that can be analysed in the laboratory.  Such analysis will still require the intervention of an expert laboratory capable of performing the test, but a number of such labs now exist around the world are presently offering a variety of DNA tests for inherited conditions.  Simple sources of DNA would be a blood sample (DNA can be extracted from the white cells present in mammalian blood), a buccal cell scrape taken from the inside of the cheek with a small nylon brush and hair follicles which also contain DNA.

There are a number of different approaches that have been used to identify the genes that are involved in different canine inherited diseases.  The first approach, known as the CANDIDATE GENE APPROACH, utilises information on diseases in other species that resemble the canine disease being studied.  PRA in the Irish setter was one of the first canine inherited diseases where the gene responsible was identified.  It had been known for some time that the setter PRA was clinically very similar, if not identical, to a form of retinitis pigmentosa (RP) found in man.  Mice with a mutation known as rcd also had a clinical condition indistinguishable from PRA and RP.  The discovery that mutation of the same gene, that encoding cyclic GMP phosphodiesterase,  caused RP in man and rcd in mouse, led researches to ask whether mutation of this same gene caused PRA in Irish setters.  The answer was ‘yes’, mutation of the cyclic GMP phosphodiesterase gene caused PRA in the Irish setter. 

The candidate gene approach represents a powerful short-cut to the identification of the mutations underlying canine inherited disease and it is not surprising that the vast majority of known canine diseases mutations have been discovered using this approach.  Unfortunately, there are not obvious candidate genes/conditions for many of the canine inherited conditions.  A second approach is therefore needed to facilitate the identification of genes involved in these conditions.  That is where the canine genome maps come into play.  Just like road maps allow us to easily navigate around the country, so genetic maps allow scientists to navigate their way along the canine chromosomes and know roughly where they are at any particular moment.  These genetic maps greatly facilitate the search for new mutant genes involved in inherited disease in the dog.  For example, take the gene responsible for copper toxicosis in the Bedlington terrier.  The genetic maps were used to roughly locate the mutant gene responsible to a small region of chromosome 10 in the dog.  Genes in this small region were then compared in clinically clear and clinically affected Bedlington terriers to identify the one mutation that results in the condition.  The gene thus identified is called the MURR1 gene.

Identifying the mutant genes involved in inherited disease is a major step toward the eradication of the mutation through selective breeding.  Knowing the mutation responsible means that a relatively simple DNA test can be devised to identify the genetic status of any dog with respect to the condition.  The availability of these simple DNA tests for inherited diseases means that dogs can be tested before they are used in a mating programme.  A small amount of tissue, either a small blood sample or the buccal cells that can readily be removed from the inside of a dog’s cheek, can be processed to produce a small amount of an individual dog’s DNA.  This can then be analysed using a particular test for the presence or absence of gene(s) known to cause a particular inherited disease.  If the disease is the result of a single gene mutation, then such a test will tell an owner whether a dog is a clear, a carrier or affected.  This information can then be taken into account when deciding which dog this should be mated to.  Obviously if the test shows a dog to be genetically clear of a disease then there are no problems, with respect to the particular condition, in mating this dog.  If the dog turns out to be a carrier, it can still be mated but the breeder should be careful to choose a mate that is genetically clear of the condition.  Under such circumstances approximately half the progeny will be clear and the other half will be carriers (assuming the condition is the result of a single recessive mutation).  However, the availability of the DNA test means that as soon as tissue can be taken from these puppies the breeder will be able to identify the clear and the carrier offspring in the litter.  Clear puppies from the litter can then be run on for subsequent breeding.  The use of DNA testing  will greatly facilitate breeders’ efforts to reduce the frequency of disease-causing mutations by selective breeding, as described above. 

The availability of a DNA test also means that under some circumstances genetically affected dogs can be bred from.   If an affected dog is mated to a DNA tested clear mate all of the offspring will be carriers.  If one of these carrier progeny is subsequently mated to another clear mate, then approximately half of this second generation will be clear and will be identifiable by DNA testing.  Thus a breeder can go from an affected dog to a clear dog in just two generations using DNA-test-driven selection process.

CATS
Breed	Condition	Company
Abyssinian	Pyruvate Kinase (PK) deficiency	PennGen
Domestic Short Haired	Glycogenosis (GSD) Type IV (glycogen branching enzyme deficiency)	PennGen
	Mucopolysaccharidosis (MPS) VIIB (glucuronidase Deficiency)	PennGen
	Pyruvate Kinase (PK) Deficiency	PennGen
Norwegian Forest Cat	Glycogenosis (GSD) Type IV (glycogen branching enzyme deficiency)	PennGen
Siamese	Mucopolysaccharidosis (MPS) VI (arylsulphatase B deficiency)	PennGen
Somali	Pyruvate Kinase (PK) Deficiency	PennGen
DOGS
Breed	Condition	Company
American Cocker Spaniel	Progressive Retinal Atrophy, prcd-1*	OptiGen
	Phosphofructokinase (PFK) Deficiency	OptiGen, Health Gene, VetGen, PennGen
Australian Cattle Dog	Progressive Retinal Atrophy, prcd-1*	OptiGen
Basenji	Pyruvate Kinase (PK) Deficiency	OptiGen, HealthGene, VetGen, PennGen
Bedlington Terrier	Copper Toxicosis*	VetGen, HealthGene, AHT, VetGen, van Haeringen
Bernese Mountain Dog	von Willebrand Disease	VetGen
Briard	Congenital Stationary Night Blindness	OptiGen, HealthGene, AHT
Cairn Terrier	Globoid Cell Leukodystrophy	HealthGene, AHT
	Haemophilia B	HealthGene
Cardigan Welsh Corgi	Progressive Retinal Atrophy, rcd-3	OptiGen, HealthGene, CamVet
Chesapeake Bay Retriever	Progressive Retinal Atrophy, prcd-1*	OptiGen
Cocker Spaniel	Progressive Retinal Atrophy, prcd-1*	OptiGen
Dachshund	Narcolepsy	OptiGen, HealthGene
Dobermann	Narcolepsy	OptiGen, HealthGene
	von Willebrand Disease	VetGen
Englsih Springer Spaniel	Fucosidosis	AHT, PennGen
	Phosphofructokinase (PFK) Deficiency	OptiGen, VetGen, HealthGene, AHT,PennGen
Golden Retriever	Muscular Dystrophy	HealthGene
Irish Setter	Canine Leucocyte Adhesion Deficiency (CLAD)	OptiGen, VetGen, HealthGene, AHT
	Progressive Retinal Atrophy, rcd-1	OptiGen, VetGen, HealthGene, AHT
Irish Red & White Setter	Canine Leucocyte Adhesion Deficiency (CLAD)	OptiGen, AHT
Kerry Blue Terrier	von Willebrand Disease	VetGen
Labrador Retriever	Cystinuria	OptiGen, PennGen
	Narcolepsy	OptiGen, HealthGene
	Progressive Retinal Atrophy, prcd-1*	OptiGen
Lhasa Apso	Renal Dysplasia*	VetGen
Manchester Terrier	von Willebrand Disease	VetGen
Mastiffs	Dominant Progressive Retinal Atrophy	OptiGen
Miniature Poodle	Progressive Retinal Atrophy, prcd-1*	OptiGen
Miniature Schnauzer	Progressive Retinal Atrophy, Type A	OptiGen
	Myotonia congenita	HealthGene, PennGen
Newfoundland	Cystinuria	OptiGen, PennGen
Nova Scotia Duck Tolling Retriever	Progressive Retinal Atrophy, prcd-1*	OptiGen
Pembroke Welsh Corgi	von Willebrand Disease	VetGen
Poodles (all varieties)	von Willebrand Disease	VetGen
Poodles (Toy)	Progressive Retinal Atrophy, prcd-1*	OptiGen
Portuguese Water Dog	Progressive Retinal Atrophy, prcd-1*	OptiGen
Samoyed	Progressive Retinal Atrophy, X-linked	OptiGen
Scottish Terrier	von Willebrand Disease	VetGen
Shetland Sheep Dog	von Willebrand Disease	VetGen
Shih Tzu	Renal Dysplasia*	VetGen
Siberian Husky	Progressive Retinal Atrophy, X-linked	OptiGen
Sloughi	Progressive Retinal Atrophy, rcd-1	OptiGen, HealthGene, AHT
Softcoated Wheaten Terrier	Renal Dysplasia*	VetGen
West Highland White Terrier	Pyruvate Kinase (PK) Deficiency	HealthGene, AHT, PennGen
	Globoid  Cell Leukodystrophy	HealthGene, AHT
CATTLE
	Condition	Company
	Bovine Leucocyte Adhesion Deficiency (BLAD)	ImmGen,van Haeringen,
	Complex Vertebral Malformation (CVM)	ImmGen, van Haeringen
	Uridine Monophosphate Deficiency (DUMPS)	ImmGen, van Haeringen
	Freemartinism	van Haeringen
	Pompes Disease	ImmGen
HORSE
	Condition	Company
	Hyperkalemic Periodic Paralysis (HYPP)	van Haeringen, ucdavis
	Lethal White Overo	ucdavis
	Severe Combined Immunodeficiency (SCID)	VetGen
	Tobario	ucdavis
PIGS
	Condition	Company
	Porcine Stress Syndrome (PSS)	van Haeringen
BIRDS
	Condition	Company
	Psitacine Beak and Feather Disease (PBFD)	van haeringen

TABLE 1        DNA TESTS AVAILABLE WORLDWIDE

All these tests are mutant-gene-based except those identified with (*) which are linkage-based DNA tests.  Contact details for the relevant companies are:

UK and Europe

AHT:               Animal Health Trust

                        Lanwades Park

                        Kentford

                        Newmarket

                        Suffolk CB8 7UU                   www.aht.org.uk

CamVet:        Dr D Sargan

                        Dept Clinical Veterinary Medicine

Madingley Road

                        Cambridge CB3 0ES           drs20@cam.ac.uk

Van Haeringen:                                            Info@vhlgenetics.com

North America

HealthGene:  Health Gene Corp

                        3300 Highway 7

                        Suite 806

                        Concord

                        ON L4K 43M3

                        Canada                                  www.healthgene.com

ImmGen:                                                        www.immgen.com

OptiGen:        OptiGen UC

                        Cornell Business and Technology Park

                        33 Thornwood Drive

                        Suite 2

                        Ithaca NY 14850

                        USA                                        www.optigen.com

PennGen:      Penn Gen Labroatories

                        3850 Spruce Street

                        Philadelphia

                        PA 19104-6010

                        USA                                        www.vet.upenn.edu then click on

‘Joesephine Dubler Genetic Disease

Testing Laboratory’

ucdavis:         Veterinary Genetics Laboratory

                        One Shields Avenue

                        Davis CA 95616-8744

                        USA                                        www.vgl.ucdavis.edu

VetGen:          Vet Gen

                        3728 Plaza Drive

                        Suite One

                        Ann Arbor

                        MI 48105

                        USA                                        www.vetgen.com

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