Whole genome sequencing identifies a homozygous nonsense mutation in the JPH2 gene in Shih Tzu dogs with progressive retinal atrophy.

Progressive retinal atrophy (PRA), common autosomal recessive disorder affecting several dog breeds including Shih Tzu, is characterized by degeneration of photoreceptors leading to blindness. To identify PRA genetic variants, three affected and 15 unaffected Shih Tzu and 20 non-Shih Tzu were recruited. Dogs underwent ophthalmologic examination and electroretinography, revealing hallmark retina pathological changes and an abnormal electroretinography in all affected dogs but not in unaffected dogs. WGS was performed. Non-synonymous homozygous variants were searched in coding regions of genes involved in retinal diseases/development; the criterion was that variants should only be present in affected dogs and should be absent in both unaffected and 46 genomes of dogs (from an available evolutionary database). Only one out of the 109 identified variants is predicted to harbor a high-impact consequence, a nonsense c.452A>C (p.L151X) in the JPH2 gene. The genotype of JPH2 variant in all 38 dogs was determined with Sanger sequencing. All three affected dogs, but none of the 35 unaffected, were homozygous for the nonsense variant. JPH2 has been previously found to be expressed in several excitable cells/tissues including retina photoreceptors. Hence, JPH2 is a candidate gene for PRA in Shih Tzu.

Genetics of Hereditary Ataxia in Scottish Terriers.

BACKGROUND: Scottish Terriers have a high incidence of juvenile onset hereditary ataxia primarily affecting the Purkinje neuron of the cerebellar cortex and causing slowly progressive cerebellar dysfunction. OBJECTIVE: To identify chromosomal regions associated with hereditary ataxia in Scottish Terriers. ANIMALS: One hundred and fifty-three Scottish Terriers were recruited through the Scottish Terrier Club of America. MATERIALS AND METHODS: Prospective study. Dogs were classified as affected if they had slowly progressive cerebellar signs. When possible, magnetic resonance imaging and histopathological evaluation of the brain were completed as diagnostic aids. To identify genomic regions connected with the disease, genome-wide mapping was performed using both linkage- and association-based approaches. Pedigree evaluation and homozygosity mapping were also performed to examine mode of inheritance and to investigate the region of interest, respectively. RESULTS: Linkage and genome-wide association studies in a cohort of Scottish Terriers both identified a region on CFA X strongly associated with the disease trait. Homozygosity mapping revealed a 4 Mb region of interest. Pedigree evaluation failed to identify the possible mode of inheritance due to the lack of complete litter information. CONCLUSION AND CLINICAL IMPORTANCE: This finding suggests that further genetic investigation of the potential region of interest on CFA X should be considered in order to identify the causal mutation as well as develop a genetic test to eliminate the disease from this breed.

Clinical characteristics of Scottie Cramp in 31 cases.

OBJECTIVE: To report the clinical features, with response to therapy and long-term outcome of Scottie Cramp as described by owners. METHODS: Owners of affected dogs provided a description of clinical signs, age of onset and disease progression. Medical records, pedigrees and videotapes of cramp episodes were evaluated. RESULTS: Thirty-one dogs were recruited; 19 showed generalised spasticity and 12 exhibited only hind limb spasticity and skipping. Episodes were noted in the first year of life in 76% of dogs and were triggered by excitement, stress and exercise. Episode frequency and severity decreased over time with behaviour modification and decreased exposure to triggers playing a role in their development. One dog was euthanased because of severe refractory signs. Fluoxetine reduced the frequency and duration of episodes in seven dogs, but not in one severely affected dog. Female dogs were over-represented with only eight affected males in the study cohort, and the presence of dogs with cerebellar degeneration in the same pedigrees may suggest a more complex mode of inheritance than previously reported. CLINICAL SIGNIFICANCE: The disorder recognised as Scottie Cramp by dog owners includes dogs with hind limb spasticity in addition to generalised cramping. Signs usually improve over time without specific treatment.

Mapping of Purkinje neuron loss and polyglucosan body accumulation in hereditary cerebellar degeneration in Scottish terriers.

A hereditary cerebellar degenerative disorder has emerged in Scottish Terriers. The aims of this study were to describe and quantify polyglucosan body accumulation and quantify Purkinje neurons in the cerebellum of affected and control dogs. The brains of 6 affected Scottish Terriers ranging in age from 8 to 15 years and 8 age-matched control dogs were examined histopathologically. Counts of Purkinje neurons and polyglucosan bodies were performed in control and affected dogs on cerebellar sections stained with periodic acid-Schiff. Affected dogs showed a significant loss of Purkinje neurons compared with control dogs (vermis: P < .0001; hemisphere: P = .0104). The degeneration was significantly more pronounced dorsally than ventrally (P < .0001). There were significantly more polyglucosan bodies in the ventral half of the vermis when compared with the dorsal half (P < .0001) in affected dogs. In addition, there were more polyglucosan bodies in the ventral half of the vermis in affected dogs than in control dogs (P = .0005). Polyglucosan bodies in all affected dogs stained positively with toluidine blue and alcian blue. Immunohistochemically, polyglucosan bodies in affected dogs were positive for neurofilament 200 kD and ubiquitin and negative for glial fibrillary acidic protein, synaptophysin, neurospecific enolase, vimentin, and S100; the bodies were negative for all antigens in control dogs. Ultrastructurally, polyglucosan bodies in 1 affected dog were non-membrane-bound, amorphous structures with a dense core. This study demonstrates significant Purkinje cell loss and increased polyglucosan bodies in the cerebellum of affected Scottish Terriers.

Hereditary cerebellar degeneration in Scottish terriers.

BACKGROUND: Hereditary cerebellar degeneration is described in several dog breeds. This heterogeneous group of diseases causes cerebellar ataxia associated with cerebellar cortical degeneration. OBJECTIVE: To report the clinical and histopathological features, and describe the mode of inheritance of hereditary cerebellar degeneration in Scottish Terriers. ANIMALS: Sixty-two affected dogs recruited through the Scottish Terrier Club of America. MATERIALS AND METHODS: Prospective, observational study: Owners of affected dogs were contacted for a description of clinical signs, age of onset, and disease progression. Medical records, videotapes of gait, and brain imaging were evaluated. When possible, necropsy was performed and the brain examined histopathologically. Prevalence of the disease was estimated and a pedigree analysis was performed to determine mode of inheritance. RESULTS: Gait abnormalities were noted in the 1st year of life in 76% of dogs, and progressed slowly; only 1 of 27 dogs dead at time of writing was euthanized because of cerebellar degeneration. Clinical signs included wide based stance, dysmetria, intention tremor, and difficulty negotiating stairs and running. Cerebellar atrophy was detected on magnetic resonance imaging. On histopathological examination, there was segmental loss of Purkinje neurons, thinning of molecular and granular layers, and polyglucosan bodies in the molecular layer. Prevalence of disease was estimated at 1 in 1,335 American Kennel Club registered Scottish Terriers. Genetic analysis results are consistent with an autosomal recessive mode of inheritance. CONCLUSION AND CLINICAL IMPORTANCE: A hereditary cerebellar degenerative disorder with a relatively mild phenotype has emerged in the Scottish Terrier. Genetic studies are needed.