Comparison of regional gene expression differences in the brains of the domestic dog and human

Comparison of the expression profiles of 2,721 genes in the cerebellum, cortex and pituitary gland of three American Staffordshire terriers, one beagle and one fox hound revealed regional expression differences in the brain but failed to reveal marked differences among breeds, or even individual dogs. Approximately 85 per cent (42 of 49 orthologue comparisons) of the regional differences in the dog are similar to those that differentiate the analogous human brain regions. A smaller percentage of human differences were replicated in the dog, particularly in the cortex, which may generally be evolving more rapidly than other brain regions in mammals. This study lays the foundation for detailed analysis of the population structure of transcriptional variation as it relates to cognitive and neurological phenotypes in the domestic dog

Genome-wide linkage study of atopic dermatitis in West Highland White Terriers

<p>Abstract</p> <p>Background</p> <p>Canine atopic dermatitis (AD) is a common, heritable, chronic allergic skin condition prevalent in the West Highland White Terrier (WHWT). In canine AD, environmental allergens trigger an inflammatory response causing visible skin lesions and chronic pruritus that can lead to secondary bacterial and yeast infections. The disorder shares many of the clinical and histopathological characteristics of human AD and represents an animal model of this disorder that could be used to further elucidate genetic causes of human AD. Microsatellite markers genotyped in families of WHWTs affected with AD were used to perform a genome-wide linkage study in order to isolate chromosomal regions associated with the disorder.</p> <p>Results</p> <p>Blood samples and health questionnaires were collected from 108 WHWTs spanning three families. A linkage simulation using these 108 dogs showed high power to detect a highly penetrant mutation. Ninety WHWTs were genotyped using markers from the Minimal Screening Set 2 (MSS-2). Two hundred and fifty six markers were informative and were used for linkage analysis. Using a LOD score of 2.7 as a significance threshold, no chromosomal regions were identified with significant linkage to AD. LOD scores greater than 1.0 were located in a 56 cM region of chromosome 7.</p> <p>Conclusions</p> <p>The study was unable to detect any chromosomal regions significantly linked to canine AD. This could be a result of factors such as environmental modification of phenotype, incorrect assignment of phenotype, a mutation of low penetrance, or incomplete genome coverage. A genome-wide SNP association study in a larger cohort of WHWTs may prove more successful by providing higher density coverage and higher statistical power.</p

Centronuclear myopathy in labrador retrievers: a recent founder mutation in the PTPLA gene has rapidly disseminated worldwide

Centronuclear myopathies (CNM) are inherited congenital disorders characterized by an excessive number of internalized nuclei. In humans, CNM results from ~70 mutations in three major genes from the myotubularin, dynamin and amphiphysin families. Analysis of animal models with altered expression of these genes revealed common defects in all forms of CNM, paving the way for unified pathogenic and therapeutic mechanisms. Despite these efforts, some CNM cases remain genetically unresolved. We previously identified an autosomal recessive form of CNM in French Labrador retrievers from an experimental pedigree, and showed that a loss-of-function mutation in the protein tyrosine phosphatase-like A (PTPLA) gene segregated with CNM. Around the world, client-owned Labrador retrievers with a similar clinical presentation and histopathological changes in muscle biopsies have been described. We hypothesized that these Labradors share the same PTPLA&lt;sup&gt;cnm&lt;/sup&gt; mutation. Genotyping of an international panel of 7,426 Labradors led to the identification of PTPLA&lt;sup&gt;cnm&lt;/sup&gt; carriers in 13 countries. Haplotype analysis demonstrated that the PTPLA&lt;sup&gt;cnm&lt;/sup&gt; allele resulted from a single and recent mutational event that may have rapidly disseminated through the extensive use of popular sires. PTPLA-deficient Labradors will help define the integrated role of PTPLA in the existing CNM gene network. They will be valuable complementary large animal models to test innovative therapies in CNM

Static posturography as a novel measure of the effects of aging on postural control in dogs

Aging is associated with impairment in postural control in humans. While dogs are a powerful model for the study of aging, the associations between age and postural control in this species have not yet been elucidated. The aims of this work were to establish a reliable protocol to measure center of pressure excursions in standing dogs and to determine age-related changes in postural sway. Data were obtained from 40 healthy adult dogs (Group A) and 28 senior dogs (Group B) during seven trials (within one session of data collection) of quiet standing on a pressure sensitive walkway system. Velocity, acceleration, root mean square, 95% ellipse area, range and frequency revolve were recorded as measures of postural sway. In Group A, reliability was assessed with intraclass correlation, and the effect of morphometric variables was evaluated using linear regression. By means of stepwise linear regression we determined that root mean square overall and acceleration in the craniocaudal direction were the best variables able to discriminate between Group A and Group B. The relationship between these two center-of-pressure (COP) measures and the dogs’ fractional lifespan was examined in both groups and the role of pain and proprioceptive deficits was evaluated in Group B. All measures except for frequency revolve showed good to excellent reliability. Weight, height and length were correlated with most of the measures. Fractional lifespan impacted postural control in Group B but not Group A. Joint pain and its interaction with proprioceptive deficits influence postural sway especially in the acceleration in the craniocaudal direction, while fractional lifespan was most important in the overall COP displacement. In conclusion, our study found that pressure sensitive walkway systems are a reliable tool to evaluate postural sway in dogs; and that postural sway is affected by morphometric parameters and increases with age and joint pain

Traumatic skull fractures in dogs and cats: A comparative analysis of neurological and computed tomographic features

Background Traumatic skull fractures (TSF) are relatively frequent in dogs and cats, but little information is available regarding their clinical and imaging features. Hypothesis/Objectives To describe the neurological and computed tomographic (CT) features of a large cohort of dogs and cats with TSF. Animals Ninety‐one dogs and 95 cats with TSF identified on CT. Methods Multicenter retrospective comparative study. Signalment, cause of trauma, fracture locations and characteristics, presence of neurological deficits, and 1‐week survival were recorded. Fractures were classified according to the extent of fragmentation and displacement. Results The cranial vault was affected more frequently in dogs (P = .003), whereas the face and base of the cranium more often was affected in cats (P < .001). Cats presented with multiple fractures more frequently (P < .001). All animals with TSF in the cranial vault were more likely to develop neurological signs (P = .02), especially when depressed fractures were present (95% confidence interval [CI], 1.7‐8.2; P = .001). Animals with TSF located only in the facial region were less likely to have neurological signs (odds ratio with Mantel‐Haenszel's method [ORMH], 0.2; 95% CI, 0.1‐0.6; P = .004). Most affected animals (84.9%) survived the first week post‐trauma. Death was more likely with fractures of the cranial vault (P = .003), especially when fragmented (P = .007) and displaced (P = .004). Conclusions and Clinical Importance Traumatic skull fracture distribution and patterns are different between dogs and cats. Cranial vault fractures were associated with neurological deficits and worse survival. The presence of TSF alone should not be considered a negative prognostic factor because most affected animals survived the first week

Bayesian model and selection signature analyses reveal risk factors for canine atopic dermatitis

Canine atopic dermatitis is an inflammatory skin disease with clinical similarities to human atopic dermatitis. Several dog breeds are at increased risk for developing this disease but previous genetic associations are poorly defined. To identify additional genetic risk factors for canine atopic dermatitis, we here apply a Bayesian mixture model adapted for mapping complex traits and a cross-population extended haplotype test to search for disease-associated loci and selective sweeps in four dog breeds at risk for atopic dermatitis. We define 15 associated loci and eight candidate regions under selection by comparing cases with controls. One associated locus is syntenic to the major genetic risk locus (Filaggrin locus) in human atopic dermatitis. One selection signal in common type Labrador retriever cases positions across the TBC1D1 gene (body weight) and one signal of selection in working type German shepherd controls overlaps the LRP1B gene (brain), near the KYNU gene (psoriasis). In conclusion, we identify candidate genes, including genes belonging to the same biological pathways across multiple loci, with potential relevance to the pathogenesis of canine atopic dermatitis. The results show genetic similarities between dog and human atopic dermatitis, and future across-species genetic comparisons are hereby further motivated

Canine Hereditary Ataxia in Old English Sheepdogs and Gordon Setters Is Associated with a Defect in the Autophagy Gene Encoding RAB24

Old English Sheepdogs and Gordon Setters suffer from a juvenile onset, autosomal recessive form of canine hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex. The clinical and histological characteristics are analogous to hereditary ataxias in humans. Linkage and genome-wide association studies on a cohort of related Old English Sheepdogs identified a region on CFA4 strongly associated with the disease phenotype. Targeted sequence capture and next generation sequencing of the region identified an A to C single nucleotide polymorphism (SNP) located at position 113 in exon 1 of an autophagy gene, RAB24, that segregated with the phenotype. Genotyping of six additional breeds of dogs affected with hereditary ataxia identified the same polymorphism in affected Gordon Setters that segregated perfectly with phenotype. The other breeds tested did not have the polymorphism. Genome-wide SNP genotyping of Gordon Setters identified a 1.9 MB region with an identical haplotype to affected Old English Sheepdogs. Histopathology, immunohistochemistry and ultrastructural evaluation of the brains of affected dogs from both breeds identified dramatic Purkinje neuron loss with axonal spheroids, accumulation of autophagosomes, ubiquitin positive inclusions and a diffuse increase in cytoplasmic neuronal ubiquitin staining. These findings recapitulate the changes reported in mice with induced neuron-specific autophagy defects. Taken together, our results suggest that a defect in RAB24, a gene associated with autophagy, is highly associated with and may contribute to canine hereditary ataxia in Old English Sheepdogs and Gordon Setters. This finding suggests that detailed investigation of autophagy pathways should be undertaken in human hereditary ataxia.American Kennel Club Canine Health Foundation (grant CHF 0407)American Kennel Club Canine Health Foundation (grant CHF 0925)Old English Sheepdog Club of AmericaTarTan Gordon Setter ClubEuropean Science Foundation (EURYI)Canine Health Information Center (DNA Repository

‘Putting our heads together’: insights into genomic conservation between human and canine intracranial tumors

Numerous attributes render the domestic dog a highly pertinent model for cancer-associated gene discovery. We performed microarray-based comparative genomic hybridization analysis of 60 spontaneous canine intracranial tumors to examine the degree to which dog and human patients exhibit aberrations of ancestrally related chromosome regions, consistent with a shared pathogenesis. Canine gliomas and meningiomas both demonstrated chromosome copy number aberrations (CNAs) that share evolutionarily conserved synteny with those previously reported in their human counterpart. Interestingly, however, genomic imbalances orthologous to some of the hallmark aberrations of human intracranial tumors, including chromosome 22/NF2 deletions in meningiomas and chromosome 1p/19q deletions in oligodendrogliomas, were not major events in the dog. Furthermore, and perhaps most significantly, we identified highly recurrent CNAs in canine intracranial tumors for which the human orthologue has been reported previously at low frequency but which have not, thus far, been associated intimately with the pathogenesis of the tumor. The presence of orthologous CNAs in canine and human intracranial cancers is strongly suggestive of their biological significance in tumor development and/or progression. Moreover, the limited genetic heterogenity within purebred dog populations, coupled with the contrasting organization of the dog and human karyotypes, offers tremendous opportunities for refining evolutionarily conserved regions of tumor-associated genomic imbalance that may harbor novel candidate genes involved in their pathogenesis. A comparative approach to the study of canine and human intracranial tumors may therefore provide new insights into their genetic etiology, towards development of more sophisticated molecular subclassification and tailored therapies in both species

Minimally invasive microsurgical decompression of an intervertebral disc protrusion in a dog.

OBJECTIVE To report the successful treatment of intervertebral disc protrusion with minimally invasive microsurgery in a large breed dog. STUDY DESIGN Retrospective case report. ANIMAL A 4-year-old, neutered male, German shepherd dog presented with chronic progressive ambulatory paraparesis and thoracolumbar pain; lumbar intervertebral disc protrusion and severe spinal cord compression at L2-L3 were diagnosed. METHODS A minimally invasive approach was used to access the target surgical area by using a muscle splitting technique and retractors. Intraoperative fluoroscopy confirmed correct placement. Magnification and illumination through a surgical microscope were used (microsurgery) to perform the spinal cord decompression by means of a foraminotomy and lateral corpectomy. RESULTS Technically, the combination of fluoroscopy and muscle splitting approach offered adequate minimally invasive access. Microsurgery allowed for precise and efficient spinal cord decompression. Clinically, no immediate postoperative neurological deterioration was observed. Opioid usage was limited to 24 hours postoperatively. Focal muscle swelling was observed postoperatively for 2 days, and hospital stay was 3 days. At 7 weeks postoperatively, neurological examination results were normal, and postoperative MRI confirmed spinal cord decompression. No complications were reported. CONCLUSION The procedure was associated with a small incision, limited muscle trauma, early improvement of the neurological status, a short hospital stay, and limited postoperative pain. CLINICAL SIGNIFICANCE This case provides evidence that minimally invasive microsurgery is an effective treatment for intervertebral disc protrusion in large breed dogs and may offer benefits regarding postoperative pain and functional recovery