The frequency of the canine leukocyte adhesion deficiency (CLAD) allele within the Irish Setter population of Australia

OBJECTIVE: To determine the frequency of the 107G-->C canine leukocyte adhesion deficiency (CLAD) mutation in Irish Setters from the Australian breeding population. METHOD: Genomic DNA was isolated from 87 Irish Setter blood samples and a region of the beta-2 integrin gene (ITGB2), encompassing the mutation, was amplified using real-time Polymerase Chain Reaction (PCR). Two fluorescently labelled probes were hybridised to the fragment, and fluorescence resonance energy transfer (FRET) was used to detect the 107G-->C mutation responsible for CLAD. RESULTS: Three new heterozygotes were identified among 87 healthy Irish Setters from Australia. All originated from a litter sired by a known heterozygote. A total of seven heterozygotes have now been identified in 92 dogs (7.6%), representing over 90% of all major breeding stock in five Australian states. Two of the heterozygotes were recently imported adult dogs and the others were their offspring. CONCLUSIONS: The frequency of the 107C allele in the Australian population of Irish Setters is lower than that in Europe. Selective breeding programs should be adopted to eliminate the mutant allele presently in two breeding lines.     

Canine leukocyte adhesion deficiency: presence of the Cys36Ser beta-2 integrin mutation in an affected US Irish Setter cross-breed dog and in US Irish Red and White Setters

Canine leukocyte adhesion deficiency (CLAD) is a primary immunodeficiency disease characterized by recurrent bacterial infections in the presence of marked leukocytosis. The disease was 1st described in the mid-1980s in a cross-breed Irish Setter Dog in the United States. It results from a defective beta-2 subunit of heterodimeric leukocyte adhesion proteins. The causative mutation for CLAD in Irish Setter Dogs from Europe has been identified as a missense mutation at base pair position 107 in the beta-2 integrin subunit gene (ITGB2) that results in an amino acid change from cysteine to serine at amino acid 36 (Cys36Ser) in the beta-2 integrin subunit protein. In the current work, the originally described dog with CLAD has been genetically tested and shown to have the same mutation as the European Irish Setters. This suggests that the mutation has been in the Irish Setter population for many generations spanning more than 2 decades. A related breed, the Irish Red and White Setter, has a history of interbreeding with Irish Setters and shares a common ancestry with the Irish Setter breed. DNA from Irish Red and White Setters residing in the United States was screened either by sequencing or by the newly developed restriction enzyme test for the Irish Setter Cys36Ser CLAD mutation. Seven of 54 dogs tested (13%) were found to be carriers of the Irish Setter CLAD mutation. Five of these were directly related to a sire from the UK, demonstrating the importation of an allele from another continent and establishing the need for genetic testing in this breed in the United States.     

Development of wheat-sensitive enteropathy in Irish Setters: morphologic changes

Morphologic changes in the small intestine were investigated during development of naturally acquired wheat-sensitive enteropathy in Irish Setters. To distinguish underlying morphologic abnormalities from nonspecific effects of intestinal damage, progeny of affected dogs reared on a normal wheat-containing diet were compared with their own littermates reared on a cereal-free diet and with age-matched clinically normal Irish Setters fed the same wheat-containing diet. Peroral jejunal biopsy specimens were taken sequentially between 4 months and 1 year of age. At 4 months of age, there were no differences in villus height, comparing the 3 groups, but increased numbers of intraepithelial lymphocytes and goblet cells were already present in biopsy specimens from the affected Irish Setters fed wheat. Dietary wheat resulted in a progressive reduction in villus height in the jejunum of affected Irish Setters from 6 months onward. Underlying morphologic abnormalities were not found, and the characteristic morphologic changes of this enteropathy were secondary to the presence of dietary wheat. However, development of partial villus atrophy was preceded by increased numbers of intraepithelial lymphocytes and goblet cells.     

Inheritance of gluten-sensitive enteropathy in Irish Setters

OBJECTIVE: To establish a model for inheritance of gluten-sensitive enteropathy (GSE) in Irish Setters. ANIMALS: 44 dogs of a 6-generation family of Irish Setters with GSE and 7 healthy Irish Setters. PROCEDURE: Phenotype of each dog was determined after oral administration of gluten in the weaning diet, using morphometric evaluation of jejunal biopsies (all generations) and measurement of small intestinal permeability by use of a lactulose-rhamnose permeation test (generations 1, 2, and 3). Overall probability for each of 4 genetic models of inheritance (autosomal recessive, autosomal dominant, sex-linked recessive, and sex-linked dominant) accounting for segregation of partial villus atrophy within the entire family was calculated. RESULTS: The autosomal recessive model was most tenable and was 56,250 times more likely to account for segregation of partial villus atrophy than the autosomal dominant model, assuming disease prevalence of 0.8%. Both sex-linked models were untenable. These conclusions were robust to the error attached to estimation of disease prevalence. High intestinal permeability without morphometric jejunal abnormalities in 4 of 20 dogs in the 3 youngest generations suggested heterogeneity of lesions associated with GSE. CONCLUSIONS: Genetic transmission of GSE is under the control of a single major autosomal recessive locus.     

Canine leukocyte adhesion deficiency colony for investigation of novel hematopoietic therapies

The genetic immunodeficiency disease canine leukocyte adhesion deficiency (CLAD) was originally described in juvenile Irish Setters with severe, recurrent bacterial infections. CLAD was subsequently shown to result from a mutation in the leukocyte integrin CD18 subunit which prevents leukocyte surface expression of the CD11/CD18 complex. We describe the development of a mixed-breed CLAD colony with clinical features that closely parallel those described in Irish Setters. We demonstrate that the early identification of CLAD heterozygotes and CLAD-affected dogs by a combination of flow cytometry and DNA sequencing allows the CLAD-affected animals to receive life-saving antibiotic therapy. The distinct clinical phenotype in CLAD, the ability to detect CD18 on the leukocyte surface by flow cytometry, and the history of the canine model in marrow transplantation, enable CLAD to serve as an attractive large-animal model for the investigation of novel hematopoietic stem cell and gene therapy strategies.     

Epidermal cell renewal in seborrheic skin of dogs

Epidermal cell renewal time of seborrheic skin was estimated in 8 adult Cocker Spaniels and 5 adult Irish Setters, using autoradiography after [3H]thymidine was given intradermally. Cell renewal time of the viable epidermis was approximately 7 days. Seemingly, the seborrheic skin observed in these Cocker Spaniels and Irish Setters was associated with an altered rate of epidermal keratinization.     

Development of wheat-sensitive enteropathy in Irish Setters: biochemical changes

Biochemical changes in the small intestine during development of naturally acquired wheat-sensitive enteropathy of Irish Setters were investigated. To distinguish primary biochemical abnormalities from secondary effects of intestinal damage, progeny of affected dogs reared on a normal wheat-containing diet were compared with their own littermates reared on a cereal-free diet and with age-matched clinically normal Irish Setters fed the same wheat-containing diet. Peroral jejunal biopsy specimens were sequentially obtained between weaning and 1 year of age; specific activity and reorientating sucrose density-gradient distribution of organelle marker enzymes were determined. Major primary biochemical abnormalities were not detected in affected progeny. In affected dogs fed wheat, there was a selective, but secondary, loss of the brush border alkaline phosphatase and aminopeptidase N activities. This loss was associated with the development of partial villus atrophy, but represented a specific effect of dietary wheat on the brush border, not merely a nonspecific effect of mucosal damage, because other brush border enzymes, including disaccharidases, were not similarly affected. Increased soluble activities of lysosomal and peroxisomal marker enzymes late in the disease process may represent alterations in these 2 organelles as a secondary consequence of mucosal damage.     

Canine leucocyte adhesion deficiency in Irish red and white setters

Seventy-six Irish red and white setter samples were tested for the recently documented CD18 point mutation which manifests as canine leucocyte adhesion deficiency (CLAD) in Irish setters. Six carrier dogs were identified, all originating from a lineage within which sporadic deaths from symptoms consistent with CLAD had been observed. This is the first demonstration that the CLAD mutation exists outside the Irish setter population, confirming that the mutation is present in a significant minority of Irish red and white setters. Routine testing by breeders to identify carrier animals will enable the eradication of CLAD from the Irish red and white setter population.     

Incidence of the gene mutation causal for rod-cone dysplasia type 1 in Irish setters in the UK

A survey to establish the UK prevalence of the gene mutation causing the rod-cone dysplasia type one (rcdl) form of generalised progressive retinal atrophy (gPRA) in Irish setters was carried out. The dogs were selected by members of two Irish setter breed societies to provide examples from most of the main breeding lines in the UK. A total of 210 Irish setters were tested and one bitch was found to be a carrier of the rcdl mutation. These results show that although a confirmed case of rcdl has not been reported in Irish setters in the UK for over a decade the gene is still present in the gene pool.     

Bacterial population and histologic changes in dogs with perianal fistula

Ages of 44 dogs with perianal fistula, ranged from 6 months to 13 years (mean, 5.2 years). German Shepherd Dogs and Irish Setters were statistically (P less than 0.01) over-represented compared with those breeds in a canine hospital population (n = 22,047) for the same period. There was a 2:1 male-to-female ratio, with 38 (86.4%) of dogs sexually intact and 6 (13.6%) of dogs neutered. Eleven types of bacterial organisms were recovered from deep perianal tissues of which Escherichia coli, Staphylococcus aureus, beta-hemolytic streptococci, and Proteus mirabilus were most common. Organisms were not recovered from 7 dogs. Of 93 isolates, 88.3% were susceptible to gentamicin, 80.5% to cephalothin, 79.2% to chloramphenicol, and 74% to trimethoprim-sulfamethoxazole. Fifty-one biopsy specimens from 44 dogs were classified as having early, intermediate-, and late-stage lesions based on the amount of fibrosis, severity of the inflammatory response, and, if present, depth of sinus tracts. In most biopsy specimens, all 3 stages were represented in the same histologic section. In 45 specimens, most inflamed lesions were in the dermis of the zona cutanea. Hidradenitis was present in 22 biopsy specimens and was associated with the formation of epithelial-lined sinus tracts.     

Enhanced intestinal permeability to 51Cr-labeled EDTA in dogs with small intestinal disease

Intestinal permeability in dogs with small intestinal disease was measured by quantitation of 24-hour urinary excretion of 51Cr-labeled EDTA following intragastric administration. Permeability was high in dogs with a variety of naturally acquired small intestinal diseases including wheat-sensitive enteropathy of Irish Setters, small intestinal bacterial over-growth, and giardiasis, and permeability was decreased after successful treatment. These findings indicate that the assessment of intestinal permeability may be a useful technique for detecting small intestinal disease and for monitoring the efficacy of treatment in dogs.     

Characterization and prevalence of cataracts in Labrador Retrievers in The Netherlands

OBJECTIVE: To assess the prevalence and distribution of types of cataract, investigate the effects of selective breeding on cataract development, and identify the relationship between posterior polar cataract and other types of cortical cataracts in Labrador Retrievers in The Netherlands. ANIMALS: 9,017 Labrador Retrievers. PROCEDURES: Records of 18,283 ophthalmic examinations performed by veterinary ophthalmologists from 1977 through 2005 were reviewed. There were 522 dogs affected by hereditary cataracts in 1 or both eyes without progressive retinal atrophy (PRA) and 166 PRA-affected dogs with cataracts. These cataracts were divided into 3 groups: posterior polar (triangular) cataract, extensive immature and mature cataract, and a miscellaneous group. Dogs with PRA were analyzed separately. RESULTS: From 1980 through 2000, the prevalence of hereditary cataracts was stable at 8%. The prevalence of cataracts in offspring of cataract-affected dogs was significantly increased, compared with the prevalence in offspring of nonaffected dogs. The distribution of types of cataract was significantly different between dogs with primary cataracts and PRA-affected dogs. Dogs with posterior polar (triangular) cataracts produced affected offspring with the same distribution of types of cataracts as the entire population of primary cataract-affected dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Cataract development in the Labrador Retriever population in The Netherlands appears to be a predominantly genetic disorder. Posterior polar (triangular) cataracts appear to be related to other types of hereditary cataract. Although there is no conclusive evidence, it seems valid to continue exclusion of all Labrador Retrievers affected by any type of primary cataract from breeding.     

BMPR-IB基因在寒泊羊群体中的增羔效应、遗传规律及育种应用分析

旨在揭示BMPR-IB基因在寒泊羊种群中的多态性及遗传学规律,探讨将BMPR-IB基因第746位碱基发生的A→G突变（FecB突变）作为分子标记进行绵羊多胎品种选育的科学性。本研究对寒泊羊育种核心群的健康种公羊、繁殖母羊、羔羊共计1 267只绵羊个体进行采血,利用PCR-RFLP方法判定个体BMPR-IB基因位点的基因型并进行群体遗传学分析。对繁殖母羊共计980胎次的产羔记录进行统计,分析FecB突变、胎次及产羔季节对胎产羔数性状的影响。统计所设计杂交组合后代共计167只健康羔羊的基因型比例。结果表明,BMPR-IB基因在寒泊羊种群中有BB、B+和++3种基因型,其基因型频率分别为1.97%、73.40%和24.63%,等位基因B和+的频率分别为38.67%、61.33%;BB、B+和++基因型繁殖母羊的平均胎产羔数分别为2.69、1.91、1.57只,目前寒泊羊种群的胎产羔数平均为1.85只;若经过品种选育使寒泊羊个体中增加一个B基因拷贝,胎产羔数预期增加0.44只;父母本杂交组合为B+×++的后代中B+和++基因型的比例为1.11：1,父母本杂交组合为B+×BB的后代中BB和B+基因型的比例为0.82：1,均符合孟德尔分离定律;预测经过6个世代的选育,可使寒泊羊种群母羊基本实现胎产羔数2只的育种目标。本研究结果为绵羊育种实践中制定选种和选配方案提供了理论基础。     

Survey of thyroglobulin autoantibodies in dogs

An enzyme-linked immunosorbent assay was used to detect autoantibodies to thyroglobulin in dogs with and without clinical evidence of thyroid disease. Autoantibodies were found in 59% of 34 clinically hypothyroid dogs, 43% of 65 dogs with nonthyroidal endocrine diseases, 47% of 64 healthy dogs closely related to antibody-positive canine hospital patients, and 13% of 1,057 canine hospital patients without endocrine disorders. Dogs with bacterial skin disease and alopecia of unknown causes had an increased prevalence of autoantibodies compared with the prevalence of autoantibodies in healthy dogs and dogs with other diseases. Three breeds of dogs, Great Danes, Irish Setters, and Old English Sheepdogs, had an increased occurrence of autoantibodies compared with that in other breeds and dogs of mixed breeding. A familial tendency to thyroid autoimmunity was demonstrated in a group of Great Dane dogs. The occurrence of autoantibodies was not influenced by age or sex. Thyroid function, as assessed by total thyroxine estimation, was depressed in hospitalized dogs compared with the thyroid function in healthy dogs, irrespective of thyroglobulin-antibody status. Two of 11 autoantibody-positive dogs monitored for an 18-month period developed low thyroxine concentration and depressed thyroid responsiveness to exogeneous thyrotropin stimulation.     

Heritability of canine hip-dysplasia score and its components in Gordon setters

Hip dysplasia (malformation of the hip joint) is an important health problem in dogs. The condition and the control scheme for Gordon Setters was organised by the British Veterinary Association (BVA) and the Kennel Club before 1976 and use hip scores. Our analyses of hip dysplasia in Gordon Setters used both hip scores and the scores for the nine components (which collectively defined the hip score). The scores for all nine components were available for 732 females and 420 males. These clinical data were merged with the Kennel Club pedigree database (animal's identity, date of birth, and also similar data for its parents, including hip scores if the parent had been tested). Regression models showed strong positive relationships between offspring and parental hip scores as well as for some component scores. The heritability of hip dysplasia (assessed using both hip scores and the major components) was significant, particularly from dams. Our research emphasizes the need for both sires and dams--particularly dams, to have zero or small hip scores. Tested parents have been used increasingly in recent years, but greater reduction in offspring hip score will require stricter selection of potential breeding stock. The models reported here provide quantitative predictions of likely health benefits from selective breeding.     

A novel mutation of the CLCN1 gene associated with myotonia hereditaria in an Australian cattle dog

BACKGROUND: Heritable myotonia is a genetic muscle disorder characterized by slow relaxation of skeletal muscles. The main clinical signs are skeletal muscle stiffness, especially after vigorous contraction, and muscle hypertrophy. Muscle stiffness may be enhanced by inactivity, and often is relieved by exercise. Myotonia can be inherited in an autosomal dominant or recessive manner (Thomsen- or Becker-type myotonia, respectively). In mice, goats, Miniature Schnauzer dogs, and most affected humans, the disorder is caused by mutations in CLCN1, which encodes the skeletal muscle voltage-gated chloride channel, Cl1C-1. HYPOTHESIS: We hypothesized that an Australian Cattle Dog with generalized muscle stiffness and hypertrophy examined at the Ontario Veterinary College would have a mutation in the CLCN1 gene. ANIMALS: A pure-bred Australian Cattle Dog from Ontario, Canada, was used. METHODS: Based on clinical signs and electromyographic test results, a diagnosis of myotonia hereditaria was made, and a muscle biopsy was collected for genetic analysis. RESULTS: Sequence data obtained from the affected dog confirmed that it was homozygous for a single base insertion in the CLCN1 coding sequence. This mutation would result in a truncated ClC-1 protein being expressed, which, based on molecular evidence from other studies, would result in functionally compromised chloride conduction in the skeletal muscles of the animal. CONCLUSIONS AND CLINICAL IMPORTANCE: To the authors' knowledge, this report describes the Ist case of myotonia in an Australian Cattle Dog and represents the 1st non-Schnauzer canine myotonia to be genetically characterized. In addition, we developed a polymerase chain reaction-based genetic screen to detect heterozygotes with this mutation in the at-large Australian Cattle Dog population.     

Progressive retinal atrophy in Abyssinian and Somali cats in the Netherlands (1981-2001)

From 1981 to 2001, 248 Abyssinian and 127 Somali cats in the Netherlands were examined for hereditary eye disease. Distinct ophthalmoscopic signs consistent with hereditary progressive retinal atrophy (PRA) were observed in 11 Abyssinian cats, and subtle signs in 3 Abyssinian cats. A familial relationship was detected in 13 out of 14 of these cats, which supports a hereditary basis to the condition. Distinct funduscopic signs of retinal degeneration were observed at a median age of 4 years. One cat with advanced retinal degeneration was only 7 months old, whereas the remaining 10 cats were between 2 and 12 years old at the time of diagnosis. These differences in the age of onset are suggestive of at least two types of PRA occurring in Abyssinian cats in the Netherlands: a dysplastic, early-onset and a late-onset retinal degeneration. A large-scale and systematic examination programme for hereditary eye disease will be necessary to assess the incidence of PRA in the Dutch population of Abyssinian and Somali cats as a whole, and to provide a basis for a preventive breeding programme.     

Investigation of the potential heritability of persistent right aortic arch in Greyhounds

In 2 successive matings of the same dam and sire in a Greyhound kennel, 1 of 6 puppies and 2 of 6 puppies were born with persistent right aortic arch (PRAA) in the first and second litters, respectively. Many congenital heart defects in dogs are believed to be heritable; however, proof of this has been difficult to obtain. Genetic predisposition to PRAA has been reported in German Shepherd Dogs and Irish Setters. The occurrence of PRAA in related Greyhounds within a kennel suggested a genetic predisposition to PRAA in a breed with which it has not been associated previously. Although the number of matings available for analysis was insufficient to conclusively prove a genetic basis for these observations, the occurrence of PRAA in puppies arising from successive matings of the same dam and sire strongly suggests that some lines of dogs of various breeds may be genetically predisposed to PRAA.     

Development and use of a polymerase chain reaction-based diagnostic test for the causal mutation of progressive retinal atrophy in Cardigan Welsh Corgis

OBJECTIVE: To develop an allele-specific polymerase chain reaction (ASPCR)-based diagnostic test for the mutation in the cyclic guanosine monophosphate phosphodiesterase alpha subunit gene (PDE6A) that causes the rcd3 form of progressive retinal atrophy (PRA) in Cardigan Welsh Corgis. ANIMALS: 1 affected homozygote, 1 unaffected carrier, 1 genotypically normal dog, and 500 unknown-PRA status Cardigan Welsh Corgis. PROCEDURE: Control blood samples were collected from Cardigan Welsh Corgis of known PRA status (ie, affected homozygote, unaffected carrier, and a genotypically normal dog) for test development. Test blood samples were collected from 500 Cardigan Welsh Corgis of unknown PRA status. Genomic DNA was used as a template in ASPCR. One pair of primers was designed to specifically amplify only the mutant allele, and another set to amplify only the wildtype allele. The PCR conditions were adjusted to ensure each reaction was 100% specific. RESULTS: The PCR conditions were identified so that each ASPCR only amplified the allele it was designed to amplify. Of the 500 Cardigan Welsh Corgis tested using the newly developed ASPCR, 457 were homozygous for the normal allele (genotypically normal), 43 were heterozygous (phenotypically normal carriers), and none were homozygous for the mutant allele. CONCLUSION AND CLINICAL RELEVANCE: A rapid, ASPCR diagnostic test able to detect the PDE6A gene mutation responsible for the rcd3 form of PRA in Cardigan Welsh Corgis was developed. The test provides a useful service for Cardigan Welsh Corgi breeders and will enable them to prevent the birth of homozygote mutant dogs.     

Insulin-secreting islet cell tumors: establishing a diagnosis and the clinical course for 25 dogs

Twenty-five dogs with insulin-secreting neoplasms of the pancreas were studied. The diagnosis in each case was determined by histologic evaluation of pancreatic tissue obtained at surgery. The breed distribution revealed that German Shepherd Dogs, Irish Setters, and Collies were most commonly represented. Physical examination, complete blood counts, serum biochemical analysis, and urinalysis were of little diagnostic value, aside from the finding of hypoglycemia in 21 of 25 dogs. Radiographs of the thorax and abdomen were noncontributory to the ultimate diagnosis. Prior to surgery, fasting immunoreactive insulin concentrations and blood glucose concentrations were studied. Insulin:glucose ratios, glucose:insulin ratios, and amended insulin:glucose ratios were determined from the insulin and glucose concentrations in a single blood sample in each of 28 trials. In addition, glucagon tolerance tests were performed on 12 dogs. The amended insulin:glucose ratios proved to be the most reliable for diagnosis. Pancreatic masses were evident at surgery in 23 of 25 dogs; the remaining 2 dogs had microscopic evidence of an islet cell tumor. Nineteen of the islet cell tumors were carcinomas and 6 were simply described as "islet cell tumors." The mean life expectancy after surgery was 12.3 months. Treatment for malignant islet cell tumours included frequent feeding glucocorticoids, and diazoxide.