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Forman O.P.,Kennel Club Genetics Center | De Risio L.,Animal Health Trust | Matiasek K.,Ludwig Maximilians University of Munich | Platt S.,University of Georgia | Mellersh C.,Kennel Club Genetics Center
Mammalian Genome

Spinocerebellar ataxia in the Italian Spinone dog breed is characterised by a progressive gait abnormality that manifests from approximately 4 months of age. The disorder shows an autosomal recessive mode of inheritance, and affected individuals are usually euthanized by one year of age on welfare grounds due to an inability to ambulate. Using a homozygosity mapping technique with six cases and six controls, we mapped the disease locus to chromosome 20 of the canine genome. Linkage analysis across an extended pedigree confirmed the association, with microsatellite C20.374 achieving a maximal LOD score of 4.41. All five genes within the disease-associated interval were exon resequenced, although no exonic candidate mutations were identified. A targeted resequencing approach was therefore adopted to sequence the entire disease-associated interval. Analysis of the sequencing data revealed a GAA repeat expansion in intron 35 of ITPR1, which was homozygous in all cases and heterozygous in obligate carriers. Partial impairment of cerebellar ITPR1 expression in affected dogs was demonstrated by immunohistochemistry. Given the association of ITPR1 mutations with spinocerebellar ataxia (SCA) type 15 (also designated SCA16) in humans and that an intronic GAA repeat expansion has been shown to cause Friedreich ataxia, the repeat expansion is an excellent candidate for the cause of spinocerebellar ataxia in the Italian Spinone. This finding represents the first naturally occurring pathogenic intronic GAA repeat expansion in a non-human species and a novel mechanism for ITPR1 associated spinocerebellar ataxia. © 2014, The Author(s). Source

Forman O.P.,Kennel Club Genetics Center | De Risio L.,Animal Health Trust | Stewart J.,Center for Preventive Medicine | Mellersh C.S.,Kennel Club Genetics Center | Beltran E.,Animal Health Trust
BMC Genetics

Background: Neonatal cerebellar cortical degeneration is a neurodegenerative disease described in several canine breeds including the Beagle. Affected Beagles are unable to ambulate normally from the onset of walking and the main pathological findings include Purkinje cell loss with swollen dendritic processes. Previous reports suggest an autosomal recessive mode of inheritance. The development of massively parallel sequencing techniques has presented the opportunity to investigate individual clinical cases using genome-wide sequencing approaches. We used genome-wide mRNA sequencing (mRNA-seq) of cerebellum tissue from a single Beagle with neonatal cerebellar cortical degeneration as a method of candidate gene sequencing, with the aim of identifying the causal mutation.Results: A four-week old Beagle dog presented with progressive signs of cerebellar ataxia and the owner elected euthanasia. Histopathology revealed findings consistent with cerebellar cortical degeneration. Genome-wide mRNA sequencing (mRNA-seq) of RNA from cerebellum tissue was used as a method of candidate gene sequencing. After analysis of the canine orthologues of human spinocerebellar ataxia associated genes, we identified a homozygous 8 bp deletion in the β-III spectrin gene, SPTBN2, associated with spinocerebellar type 5 in humans. Genotype analysis of the sire, dam, ten clinically unaffected siblings, and an affected sibling from a previous litter, showed the mutation to fully segregate with the disorder. Previous studies have shown that β-III spectrin is critical for Purkinje cell development, and the absence of this protein can lead to cell damage through excitotoxicity, consistent with the observed Purkinje cell loss, degeneration of dendritic processes and associated neurological dysfunction in this Beagle.Conclusions: An 8 bp deletion in the SPTBN2 gene encoding β-III spectrin is associated with neonatal cerebellar cortical degeneration in Beagle dogs. This study shows that mRNA-seq is a feasible method of screening candidate genes for mutations associated with rare diseases when a suitable tissue resource is available. © 2012 Forman et al.; licensee BioMed Central Ltd. Source

Lewis T.,Kennel Club Genetics Center | Swift S.,Northwest Surgeons | Woolliams J.A.,Roslin Institute | Blott S.,Kennel Club Genetics Center
Veterinary Journal

Mixed model analysis of 1252 records of cardiac auscultation of 4- to 5-year-old Cavalier King Charles spaniels (CKCS) from 1991 to 2008 in conjunction with the Kennel Club pedigree records of all dogs registered from the mid 1980s to September 2007 was used to estimate variance parameters of premature mitral valve disease (MVD). Data were limited to dogs ≥4 and <5. years of age to ensure diagnostic distinction between early and late onset MVD. Cardiac murmurs were detected in 108/1252 (8.6%) dogs. Heritability estimates of 0.67 (standard error, SE 0.071) for the grade of murmur and 0.33 (SE 0.072) for the presence/absence of murmur were calculated. The variance due to clinician was 0.02 (SE 0.012) for grade and 0.03 (SE 0.017) for presence/absence of murmur. These results indicate that the presence and severity of MVD, as assessed by cardiac auscultation, in 4- to 5-year-old CKCS is highly heritable and that selection against the disease should be successful. © 2010 Elsevier Ltd. Source

Lewis T.W.,Kennel Club Genetics Center | Ilska J.J.,Roslin Institute | Blott S.C.,Kennel Club Genetics Center | Woolliams J.A.,Roslin Institute
Veterinary Journal

A linear mixed model analysis of elbow and hip score data from UK Labrador retrievers was used to estimate the heritability of elbow score (0.16-0.19) and to determine a moderate and beneficial genetic correlation with hip score (0.40). A small improvement in the genetic trend of elbow score was observed during the years 2000-2008, equivalent to avoiding only the worst 3-4% of scored dogs for breeding, but close to what may have been anticipated if the current British Veterinary Association-approved guidelines were followed.Calculations suggested that a correlated response to indirect selection on hip score may elicit a greater response than direct selection on elbow score and that the genetic trend in elbow score may be explained as a consequence of the stronger selection pressure that has been placed on hip score. Increases in the accuracy of estimated breeding values for elbow score of 4-7% for dogs with elbow data only and 7-11% for dogs with both hip and elbow score were observed from bivariate analysis of elbow and hip data. A selection index confirmed the benefits of bivariate analysis of elbow and hip score data by identifying increases in accuracy (directly related to the response to selection) of 14% from the use of optimum coefficients compared to use of hip data only.The quantified genetic correlation means that hip score effectively acts as a 'secondary indicator' of elbow score in this breed and the preponderance of hip data means that it acts as a major source of information that may be used to improve the accuracy of estimates of genetic risk for elbow dysplasia. © 2011 Elsevier Ltd. Source

Forman O.P.,Kennel Club Genetics Center | De Risio L.,Center for Small Animal Studies | Mellersh C.S.,Kennel Club Genetics Center

Spinocerebellar ataxia (SCA) in the Parson Russell Terrier (PRT) dog breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain), was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans. © 2013 Forman et al. Source

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