Advances in the molecular understanding of canine retinal diseases

Retinal dystrophies are a common cause of blindness in purebred dogs. Progressive retinal atrophy, the canine equivalent of retinitis pigmentosa in humans, is the most common dystrophy. Molecular studies have led to the identification of the genetic defect underlying some forms of progressive retinal atrophy and the mapping of the chromosomal location of others. Additionally, the gene mutation that causes a severe retinal dystrophy in the briard, which is the equivalent of Leber congenital amaurosis in humans, has been identified. These advances have led to the development of DNA-based diagnostic tests for some retinal dystrophies, thus facilitating their eradication. The study of these dystrophies in dogs has also provided useful information about the equivalent diseases in humans. Recently, gene therapy has been used to restore vision to dogs with a retinal dystrophy due to a mutation in the RPE65 gene. Such studies are important in the quest to develop therapies for similar conditions in humans.     

Identification of mutations in HSF4 in dogs of three different breeds with hereditary cataracts

Cataracts are a leading cause of blindness in both dogs and humans. Mutations in several genes have been associated with inherited forms of human cataract, but no mutations have been identified as the cause of any form of canine inherited cataract. We have used a candidate gene approach to investigate 20 genes, known to be associated with cataract in humans, for their potential association with the development of hereditary cataract (HC) in dogs. We have identified mutations in the HSF4 gene in Staffordshire Bull Terriers, Boston Terriers and Australian Shepherds affected by HC. Interestingly, different mutations in this single gene may be causing a recessive form of cataract in Staffordshire Bull Terriers and Boston Terriers and a dominant cataract in Australian Shepherds. Identification of the mutations that cause HC in these three breeds provides a method of controlling the disease within populations at risk using a simple diagnostic test, and also establishes cataract in these breeds as models for their human counterparts.     

Canine inherited retinal degenerations: update on molecular genetic research and its clinical application

Inherited retinal degenerations in the dog include generalised progressive retinal atrophy, retinal pigment epithelial dystrophy, congenital stationary night blindness and day blindness (hemeralopia). The clinical phenotype and pathology of these diseases closely resemble some types of human inherited retinal degeneration, in particular retinitis pigmentosa, one of the most common inherited causes of blindness in man. Molecular genetic investigations aim to identify the genetic mutations underlying the canine inherited retinal degenerations. Two major research strategies, candidate gene analysis and linkage analysis, have been used. To date, candidate gene analysis has definitively identified the genetic mutations underlying nine inherited retinal degenerations, each in a different breed of dog, and linkage studies have identified genetic markers for a further retinal degeneration which is found in at least six different breeds. This review outlines the research strategy behind candidate gene and linkage studies and summarises recent results in the search for genetic causes of canine inherited retinal degenerations. The aim is to increase awareness of this rapidly changing field and to show how the research can be used to develop genetic tests for these diseases and thereby reduce the incidence of inherited eye disease in dogs.     

Dilated cardiomyopathy (DCM) in dogs--pathological, clinical, diagnosis and genetic aspects

Dilated cardiomyopathy (DCM) is a heart disease which is often found in humans and animals. The age of onset of this progressive disease varies between 3 and 7 years of age. A juvenile form of DCM has been found in Portuguese Water Dogs and Doberman Pinscher Dogs. Some breeds such as Doberman pinscher, Newfoundland, Portuguese Water dog, Boxer, Great Dane, Cocker Spaniel and Irish Wolfhound exhibit a higher prevalence to DCM. There also seems to be a sex predisposition as male dogs are affected more often than female dogs and in Great Danes an X-linked recessive inheritance is likely. In Newfoundland and Boxer an autosomal dominant inheritance was found whereas an autosomal recessive inheritance was described in Portuguese Water Dogs. Atrial fibrillation as a cause or consequence of DCM is assumed for certain breeds. The causes of DCM are widely unknown in dogs. A genetic basis for this heart disease seems to exist. Apart from a few exceptions the mode of inheritance and the possible underlying gene mutations are not known for DCM in dogs. In humans mutations in several genes responsible for DCM have been identified. Comparative genetic analyses in dogs using genes causing DCM in men and a genome-wide scan with anonymus markers were not able to detect causative mutations or genomic regions harboring gene loci linked to DCM. The investigation of the genetic basis of canine DCM may lead to new insights into the pathogenesis of DCM and may result in new therapeutic approaches and breeding strategies.     

Retinal degeneration in the dog and cat

Retinal degenerations in the dog and cat are an important cause of blindness in these species. Particularly in the dog, many retinal degenerations, collectively called progressive retinal atrophy, seen in clinical practice are inherited. The clinical signs, electrophysiological findings, pathology, and underlying biochemical defects in the retina vary from breed to breed. Specific categories of inherited retinal degeneration are now recognized, and classified into early onset photoreceptor dysplasias, late-onset retinal degenerations, or retinal degenerations secondary to primary RPE dystrophy. As new inherited retinal degenerations are reported in different breeds they can generally be assigned to one these categories. Other causes of retinal degeneration include nutritional deficiencies, glaucoma, inflammation, ischemia, and toxins. Idiopathic retinal degeneration occurs in the dog with some frequency.     

Give a dog a genome

In 2004 the dog became only the fifth mammal to have its entire genome fully sequenced. The canine genome was sequenced in the hope that it would help scientists understand the complex evolutionary mechanisms that shape genes and genomes and provide a powerful tool for identifying genetic factors that contribute to human health and disease. It is expected that over the coming years the genome of man's best friend will help in the understanding of the genetic cause of many inherited diseases that humans and dogs have in common. Not only of obvious benefit to humans, these studies will enable the development of DNA diagnostic tests that breeders can use to identify which of their dogs carry mutations that put them at risk of developing particular conditions and thus, over time, eliminate those diseases from the breed.     

Characterization of feline hereditary retinal dystrophies using clinical, functional, structural and molecular genetic studies

Only in recent years have specific mutations been elucidated for feline hereditary retinal dystrophies. Molecular genetic characterization of feline diseases has so far been a slow process but with a full genome sequence for the cat recently completed and the development of a feline single nucleotide polymorphism chip, the characterization of feline monogenic disorders will be significantly simplified. This review summarizes current knowledge with regard to specific hereditary retinal dystrophies in cats and gives an overview of how cats can be used as models in translational research.     

Congenital sensorineural deafness in dogs: a molecular genetic approach toward unravelling the responsible genes

Deafness is often diagnosed in different dog breeds and has been identified as a significant problem for breeders, owners and clinicians. The aetiology can be inherited or acquired, and a distinction must be made between sensorineural and conductive forms of deafness. This paper provides a brief overview of the varieties of findings in different dog breeds and in one breed in particular including prevalence, phenotypic and gender associations, histology, modes of inheritance and the number of contributing genes in congenital sensorineural deafness. We have also described molecular genetic approaches to canine hearing loss and discuss how comparative genomics could help reduce the prevalence of deafness in affected breeds leading to new insights into the molecular mechanisms of auditory function in both dogs and humans.     

Analysis of a deletion in the nephronophthisis 4 gene in different dog breeds

Cone‐rod dystrophy is a progressive inherited retinal degenerative disorder that occurs in humans and dogs. The deletion in the nephronophthisis 4 (NPHP4) gene was established as a causative mutation in standard wire‐haired Dachshunds. We analyzed all varieties of Dachshunds from the Czech Republic and five other dog breeds and found that the deletion in the NPHP4 (in heterozygous state) is present not only in standard‐, but also in miniature wire‐haired Dachshunds, but not in other varieties of Dachshunds or in other breeds.     

Corneal dystrophy in the dog and cat

Two types of epithelial dystrophy have been described in dogs, one each in the Boxer and Shetland Sheepdog breeds, both of which can be associated with corneal erosions. Medical therapy is recommended when erosions or tear film abnormalities are present. Stromal dystrophies documented in dogs appear to be a primary lipid deposition in various layers of the stroma, depending on the breed. Stromal dystrophies seldom lead to loss of vision, but vision loss has been observed in middle aged Airedale Terriers and aged Siberian Huskies. Treatment is usually unnecessary. The dog demonstrates two types of endothelial dystrophy, one of which (posterior polymorphous dystrophy in the American Cocker Spaniel) does not lead to corneal edema. Endothelial dystrophy observed in the Boston Terrier, Chihuahua, and other breeds is associated with progressive corneal edema, which can lead to bullous keratopathy and corneal erosions. Stromal and endothelial dystrophies, both of which are associated with rapid progression of corneal edema, occur rarely in the cat. Treatment of dystrophies with progressive corneal edema is symptomatic and palliative.     

Examination of candidate genes for hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers

Inherited hypoadrenocorticism occurs in some dog breeds including the Nova Scotia Duck Tolling Retriever (NSDTR) and is thought to be due to an immune attack on the adrenal glands. The genetic cause of this disorder in dogs has not been identified; however, many genes have been associated with hypoadrenocorticism and other immune-mediated conditions in humans including AIRE, BAFF, Casp10, CD28, CTLA-4, FASL, PTPN22, and TNFRSF6B. Microsatellite marker loci were analysed for linkage with the disease phenotype in a pedigree of NSDTRs and excluded all genes examined, the exception being CTLA-4, which was neither excluded nor shown to be associated by this analysis. Thus, genes associated with hypoadrenocorticism in humans were not linked with the condition in the dog. Further examination is necessary to identify the genetic cause of inherited hypoadrenocorticism in dogs and this may reveal a novel gene not yet implicated with immune-mediated disease.     

Genetic analysis of presumed inherited eye diseases in Tibetan Terriers

We analysed the systematic environmental influences and the additive genetic variation for the presumed inherited eye diseases (PIED), membrana pupillaris persistens, distichiasis, primary lens luxation, non-congenital cataract, and progressive retinal atrophy, in Tibetan Terriers. Data were obtained from the International Kennel Club for Tibetan dog breeds in Germany. PIED were recorded in the years 1987 to 2001 by standardised protocols of the Dortmunder Kreis, the association for diagnosis of inherited eye diseases in animals (DOK). The material included 849 Tibetan Terriers from 596 litters in 203 different kennels. The multivariate linear animal model using residual maximum likelihood methods regarded the fixed effects of sex, birth year, experience of the veterinary ophthalmologist, litter size, percentage of examined dogs per litter, inbreeding coefficient, and age at examination. The common environment of the litter and the additive genetic effect of the animal were taken into account as randomly distributed effects. The heritability estimates for PIED in Tibetan Terriers were h2=0.17+/-0.04 (membrana pupillaris persistens), h2=0.04+/-0.03 (distichiasis), h2=0.13+/-0.04 (primary lens luxation), h2=0.13+/-0.04 (non-congenital cataract), and h2=0.49+/-0.08 (progressive retinal atrophy). The additive genetic correlation between non-congenital cataract and progressive retinal atrophy was highly positive rg=0.76+/-0.11, while that between membrana pupillaris persistens and progressive retinal atrophy rg=-0.43+/-0.14 was highly negative. The number of examinations performed by the veterinary ophthalmologists was associated with higher heritabilities for non-congenital cataract and progressive retinal atrophy. We concluded from our analysis that all investigated PIED in Tibetan Terriers are genetically influenced.     

Retinal ganglion cell (RGC) death in glaucomatous beagles is not associated with mutations in p53 and NTF4 genes

Background Glaucoma in humans is a second leading cause of irreversible vision loss in the world and can affect all age groups as well as all populations. The precise mechanism of retinal ganglion cell (RGC) death and progressive degeneration of optic nerve in glaucoma is not understood. It has been suggested that apoptosis is the common pathway that leads to the death of RGCs in glaucoma and that neurotrophin 4 (NTF4) protein plays a role in the protection of RGCs by activating tyrosine kinase receptors. Additionally, one previous study suggested that p53 codon 72 polymorphism (R72P) might have a greater susceptibility to apoptosis in some ethnic population. Glaucoma also occurs in dogs, and the primary glaucoma in beagles is inherited as an autosomal recessive trait. Although recently a candidate gene has been isolated, the mechanism underlying RGC death is not understood. Method To understand whether the same p53 and NTF4 pathway mechanism is involved in a beagle model of glaucoma, we have isolated NTF4 gene from dog and analyzed both p53 and NTF4 genes for mutations in glaucomatous animals. Results Our analyses failed to identify any disease-causing mutations in both genes with the exception of two polymorphisms in NTF4 gene. However, these are not pathogenic changes because they are also present in normal animals and are not segregated with the disease. Conclusion These results suggest that impaired neurotrophin signaling or compromised trophic support to the retina and p53-mediated apoptosis may not be the underlying mechanism of RGCs death in a beagle model of glaucoma.     

Hypertrophic cardiomyopathy in the Sphynx cat: a retrospective evaluation of clinical presentation and heritable etiology

Hypertrophic cardiomyopathy is an inherited disease in some feline breeds including the Maine Coon and Ragdoll. In these breeds, distinct causative genetic mutations have been identified. The two breeds appear to have slightly different clinical presentations, including age of diagnosis. The observation that these two breeds may have different clinical presentations, as well as different genetic mutations, suggests that hypertrophic cardiomyopathy is a diverse disease in the cat. Hypertrophic cardiomyopathy is poorly described in the Sphynx. The objective of this study was to phenotypically characterize Sphynx hypertrophic cardiomyopathy and to evaluate for a familial etiology. Records of 18 affected cats (11 female, seven male) were evaluated. Age of affected cats ranged from 0.5 to 7 years (median, 2 years). Four affected cats were from a single family and included an affected cat in each of four generations (three females, one male). Further studies are warranted to evaluate for a causative mutation and better classify the phenotypic expression.     

NHLRC1 homozygous dodecamer expansion in a Newfoundland dog with Lafora disease

Lafora disease is a genetic disease caused, in humans, by mutations in EPM2A and NHLRC1 genes, resulting in accumulation of polyglucosan bodies within neurons. Affected subjects present progressive neurological signs characterised primarily by myoclonic epilepsy. In dogs, Lafora disease has been described mainly in miniature wire-haired Dachshunds, where a dodecamer expansion in NHLRC1 gene has been identified. The same mutation has then been detected in the Basset Hound, Beagle, Chihuahua and Pembroke Welsh Corgi breeds. This is the first case of a Newfoundland dog with myoclonic epilepsy diagnosed with Lafora disease based on confirmed dodecamer expansion in the NHLRC1 gene. Lafora disease is being progressively recognised in different unrelated breeds suggesting a wider distribution in the canine population than previously thought.     

Light at the end of the tunnel? Advances in the understanding and treatment of glaucoma and inherited retinal degeneration

Glaucoma and inherited retinal degeneration/dystrophy are leading causes of blindness in veterinary patients. Currently, there is no treatment for the loss of vision that characterizes both groups of diseases. However, this reality may soon change as recent advances in understanding of the disease processes allow researchers to develop new therapies aimed at preventing blindness and restoring vision to blind patients. Elucidating the molecular mechanisms of retinal ganglion cell death in glaucoma patients has led to the development of neuroprotective drugs which protect retinal cells and their function from the disastrous effects of elevated pressure. Identification of the genetic mutation responsible for inherited degenerations and dystrophies of the outer retina has enabled researchers using gene therapy to restore vision to blind dogs. Other patients may benefit from retinal transplantation, stem cell therapy, neuroprotective drugs, nutritional supplementation and even retinal prostheses. It is possible that soon it will be possible to restore sight to some blind patients.     

Analysis of prevalence of presumed inherited eye diseases in Entlebucher Mountain Dogs

We analyzed the prevalence of the presumed inherited eye diseases (PIED) noncongenital cataract and progressive retinal atrophy in the Entlebucher Mountain Dog for systematic environmental influences and the additive genetic variation. Multivariate linear animal models using residual maximum likelihood methods and multivariate threshold animal models using Gibbs sampling in Bayesian analyses were used to estimate variance and covariance components. Data were obtained from the kennel club for Swiss Mountain Dog breeds in Germany. PIED were recorded using the standardized protocols of the Dortmunder Kreis, the German panel of the European Eye Scheme for Diagnosis of Inherited Eye Diseases in Animals (DOK). The material included 515 Entlebucher Mountain Dogs from 344 litters at 77 different kennels. Veterinary diagnoses for PIED were from the years 1981-2001. Pedigree information was available for up to nine generations. The multivariate animal model regarded the fixed effects of sex, birth year, experience of the veterinary ophthalmologist, litter size, percentage of examined dogs per litter, inbreeding coefficient and age at examination. The common environment of the litter and the additive genetic effect of the animal were taken into account as randomly distributed effects. The heritability estimates for PIED in the Entlebucher Mountain Dog were h2=0.15+/-0.06 (noncongenital cataract), and h2=0.34+/-0.08 (progressive retinal atrophy) in the linear model and h2=0.32+/-0.05 (noncongenital cataract) and h2=0.59+/-0.03 (progessive retinal atrophy) in the threshold model. The additive genetic correlation between noncongenital cataract and progressive retinal atrophy was moderately positive (r(g)=0.54+/-0.08) in the threshold model. The number of examinations performed by the veterinary ophthalmologists was associated with slightly higher heritabilities for noncongenital cataract and considerably higher heritabilities for progressive retinal atrophy. The investigated PIED in the Entlebucher Mountain Dog are genetically influenced and the size of the genetic parameters estimated may be sensitive to the accuracy of the diagnosis and how the data were collected.     

Inherited eye disease in the dog and cat

This paper describes the more common inherited eye conditions in the dog and cat, paying particular attention to the newer conditions, not all of which have previously been reported in the literature. These newer conditions include entropion in the shar pei, microphthalmos in the dobermann and miniature schnauzer, cataract in the German shepherd dog and Norwegian buhund, progressive retinal atrophy in the Tibetan terrier, Tibetan spaniel, miniature longhaired dachshund and two forms in the Abyssinian cat, multifocal retinal dysplasia in the English springer spaniel and other breeds, persistent hyperplastic primary vitreous in the Staffordshire bull terrier and dobermann and optic nerve hypoplasia in the toy poodle. Anatomical classification presents a convenient means of describing these conditions which may affect the whole globe, the eyelids, the nictitating membrane, the nasolacrimal duct system, the conjunctiva, the cornea, the aqueous, the iris, the lens and zonule, the vitreous, the retina, the choroid and sclera and the optic nerve.     

A review on prolificacy genes in sheep

Ovulation rate and litter size are important reproduction traits in sheep and are of high economic value. Reproduction traits typically have low to medium heritabilities and do not exhibit a noticeable response to phenotypic selection. Therefore, inclusion of genetic information of the genes associated with reproductive ability could efficiently enhance the selection response. The most important major genes affecting prolificacy and their genetic diversities in different sheep breeds were reviewed. Different causative mutations with major effects on reproductive traits including ovulation rate and litter size have been found in various sheep breeds around the world. A general overview of the studies on main prolificacy genes showed that some alleles may express different phenotypic effects in different breeds, and thus, further studies on epistatic effects are necessary for more understanding of genetic control of reproductivity in sheep. Regarding the polygenic control of fertility traits, application of new high‐throughput technologies to find new variants is essential for future studies. Moreover, genomewide association studies and genomic best linear unbiased predictions of breeding values are likely to be effective tools for genetic improvement of sheep reproductive performance traits.     

Control of inherited retinal degeneration in dogs and cats in the United Kingdom

The term progressive retinal atrophy (PRA) is synonymous with inherited blindness in both dogs and cats as the result of retinal degeneration. In fact several types of degeneration occur within this complex, but the ophthalmoscopic features are well recognised and practical disease control is possible through routine examination. However, effective measures demand the whole-hearted support of the breeds involved, and only extensively applied examination schemes in which there is a central pooling and use of results are likely to produce the degree of disease control necessary, Test-mating and electrorelinograph (ERG) examination also have a part to play in the identification of normal genotypes, but the application of routine ophthalmoscopic examination, perhaps associates with Kennel Club registration, currently offers the most effective way forward.