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

‘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

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

Ambulation in Dogs With Absent Pain Perception After Acute Thoracolumbar Spinal Cord Injury.

Acute thoracolumbar spinal cord injury (SCI) is common in dogs frequently secondary to intervertebral disc herniation. Following severe injury, some dogs never regain sensory function to the pelvic limbs or tail and are designated chronically "deep pain negative." Despite this, a subset of these dogs develop spontaneous motor recovery over time including some that recover sufficient function in their pelvic limbs to walk independently without assistance or weight support. This type of ambulation is commonly known as "spinal walking" and can take up to a year or more to develop. This review provides a comparative overview of locomotion and explores the physiology of locomotor recovery after severe SCI in dogs. We discuss the mechanisms by which post-injury plasticity and coordination between circuitry contained within the spinal cord, peripheral sensory feedback, and residual or recovered supraspinal connections might combine to underpin spinal walking. The clinical characteristics of spinal walking are outlined including what is known about the role of patient or injury features such as lesion location, timeframe post-injury, body size, and spasticity. The relationship between the emergence of spinal walking and electrodiagnostic and magnetic resonance imaging findings are also discussed. Finally, we review possible ways to predict or facilitate recovery of walking in chronically deep pain negative dogs. Improved understanding of the mechanisms of gait generation and plasticity of the surviving tissue after injury might pave the way for further treatment options and enhanced outcomes in severely injured dogs

Clinical Trial Design-A Review-With Emphasis on Acute Intervertebral Disc Herniation.

There is a clear need for new methods of treatment of acute disc herniation in dogs, most obviously to address the permanent loss of function that can arise because of the associated spinal cord injury. Clinical trials form the optimal method to introduce new therapies into everyday clinical practice because they are a reliable source of unbiased evidence of effectiveness. Although many designs are available, parallel cohort trials are most widely applicable to acute disc herniation in dogs. In this review another key trial design decision-that between pragmatic and explanatory approaches-is highlighted and used as a theme to illustrate the close relationship between trial objective and design. Acute disc herniation, and acute spinal cord injury, is common in dogs and there is a multitude of candidate interventions that could be trialed. Most current obstacles to large-scale clinical trials in dogs can be overcome by collaboration and cooperation amongst interested veterinarians

Bladder and Bowel Management in Dogs With Spinal Cord Injury.

Spinal cord injury in companion dogs can lead to urinary and fecal incontinence or retention, depending on the severity, and localization of the lesion along the canine nervous system. The bladder and gastrointestinal dysfunction caused by lesions of the autonomic system can be difficult to recognize, interpret and are easily overlooked. Nevertheless, it is crucial to maintain a high degree of awareness of the impact of micturition and defecation disturbances on the animal's condition, welfare and on the owner. The management of these disabilities is all the more challenging that the autonomic nervous system physiology is a complex topic. In this review, we propose to briefly remind the reader the physiology of micturition and defecation in dogs. We then present the bladder and gastrointestinal clinical signs associated with sacral lesions (i.e., the L7-S3 spinal cord segments and nerves) and supra-sacral lesions (i.e., cranial to the L7 spinal cord segment), largely in the context of intervertebral disc herniation. We summarize what is known about the natural recovery of urinary and fecal continence in dogs after spinal cord injury. In particular we review the incidence of urinary tract infection after injury. We finally explore the past and recent literature describing management of urinary and fecal dysfunction in the acute and chronic phase of spinal cord injury. This comprises medical therapies but importantly a number of surgical options, some known for decades such as sacral nerve stimulation, that might spark some interest in the field of spinal cord injury in companion dogs

Prognostic Factors in Canine Acute Intervertebral Disc Disease.

Knowledge of the prognosis of acute spinal cord injury is critical to provide appropriate information for clients and make the best treatment choices. Acute intervertebral disc extrusions (IVDE) are a common cause of pain and paralysis in dogs with several types of IVDE occurring. Important prognostic considerations are recovery of ambulation, return of urinary and fecal continence, resolution of pain and, on the negative side, development of progressive myelomalacia. Initial injury severity affects prognosis as does type of IVDE, particularly when considering recovery of continence. Overall, loss of deep pain perception signals a worse outcome. When considering Hansen type 1 IVDE, the prognosis is altered by the choice of surgical vs. medical therapy. Concentration of structural proteins in the plasma, as well as inflammatory mediators, creatine kinase, and myelin basic protein in the cerebrospinal fluid (CSF) can provide additional prognostic information. Finally, cross-sectional area and length of T2 hyperintensity and loss of HASTE signal on MRI have been associated with outcome. Future developments in plasma and imaging biomarkers will assist in accurate prognostication and optimization of patient management