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Congenital deafness in the domestic dog is usually related to the presence of white pigmentation, which is controlled primarily by the piebald locus on chromosome 20 and also by merle on chromosome 10. Pigment-associated deafness is also seen in other species, including cats, mice, sheep, alpacas, horses, cows, pigs, and humans, but the genetic factors determining why some piebald or merle dogs develop deafness while others do not have yet to be determined. Here we perform a genome-wide association study (GWAS) to identify regions of the canine genome significantly associated with deafness in three dog breeds carrying piebald: Dalmatian, Australian cattle dog, and English setter. We include bilaterally deaf, unilaterally deaf, and matched control dogs from the same litter, phenotyped using the brainstem auditory evoked response (BAER) hearing test. Principal component analysis showed that we have different distributions of cases and controls in genetically distinct Dalmatian populations, therefore GWAS was performed separately for North American and UK samples. We identified one genome-wide significant association and 14 suggestive (chromosome-wide) associations using the GWAS design of bilaterally deaf vs. control Australian cattle dogs. However, these associations were not located on the same chromosome as the piebald locus, indicating the complexity of the genetics underlying this disease in the domestic dog. Because of this apparent complex genetic architecture, larger sample sizes may be needed to detect the genetic loci modulating risk in piebald dogs. [ABSTRACT FROM AUTHOR]

A form of hereditary cerebellar ataxia has recently been described in the Norwegian Buhund dog breed. This study aimed to identify the genetic cause of the disease. Whole-genome sequencing of two Norwegian Buhund siblings diagnosed with progressive cerebellar ataxia was carried out, and sequences compared with 405 whole genome sequences of dogs of other breeds to filter benign common variants. Nine variants predicted to be deleterious segregated among the genomes in concordance with an autosomal recessive mode of inheritance, only one of which segregated within the breed when genotyped in additional Norwegian Buhunds. In total this variant was assessed in 802 whole genome sequences, and genotyped in an additional 505 unaffected dogs (including 146 Buhunds), and only four affected Norwegian Buhunds were homozygous for the variant. The variant identified, a T to C single nucleotide polymorphism (SNP) (NC_006585.3:g.88890674T>C), is predicted to cause a tryptophan to arginine substitution in a highly conserved region of the potassium voltage-gated channel interacting protein KCNIP4. This gene has not been implicated previously in hereditary ataxia in any species. Evaluation of KCNIP4 protein expression through western blot and immunohistochemical analysis using cerebellum tissue of affected and control dogs demonstrated that the mutation causes a dramatic reduction of KCNIP4 protein expression. The expression of alternative KCNIP4 transcripts within the canine cerebellum, and regional differences in KCNIP4 protein expression, were characterised through RT-PCR and immunohistochemistry respectively. The voltage-gated potassium channel protein KCND3 has previously been implicated in spinocerebellar ataxia, and our findings suggest that the Kv4 channel complex KCNIP accessory subunits also have an essential role in voltage-gated potassium channel function in the cerebellum and should be investigated as potential candidate genes for cerebellar ataxia in future studies in other species. Author summary: Hereditary ataxias, which are a group of disorders characterised by incoordination of movement, are typically incurable and there are often no disease-modifying treatments available. Canine hereditary ataxias are a notable group of movement disorders in dogs, and represent well characterised naturally occurring disease models of ataxia that can help improve our understanding of the underlying biology of the disorder in both dogs and humans. We used the whole genome sequences of two affected siblings to investigate the genetic cause of a slowly progressive form of hereditary ataxia in the Norwegian Buhund dog breed, and identified a single base change within the KCNIP4 gene. We have characterised the expression of KCNIP4 in the dog, and investigated the effect of the identified mutation. This gene has not previously been implicated in inherited ataxia in any species, and our findings suggest that this and related genes represent potential candidates for ataxia in future studies in other species. Our findings will allow dog breeders to avoid producing affected dogs, reduce the disease allele frequency, and eventually eliminate the disease from the breed, through the use of a DNA test. [ABSTRACT FROM AUTHOR]

Four full-sibling intact male Miniature Poodles were evaluated at 4–19 months of age. One was clinically normal and three were affected. All affected dogs were reluctant to exercise and had generalised muscle atrophy, a stiff gait and a markedly elevated serum creatine kinase activity. Two affected dogs also showed poor development, learning difficulties and episodes of abnormal behaviour. In these two dogs, investigations into forebrain structural and metabolic diseases were unremarkable; electromyography demonstrated fibrillation potentials and complex repetitive discharges in the infraspinatus, supraspinatus and epaxial muscles. Histopathological, immunohistochemical and immunoblotting analyses of muscle biopsies were consistent with dystrophin-deficient muscular dystrophy. DNA samples were obtained from all four full-sibling male Poodles, a healthy female littermate and the dam, which was clinically normal. Whole genome sequencing of one affected dog revealed a >5 Mb deletion on the X chromosome, encompassing the entire DMD gene. The exact deletion breakpoints could not be experimentally ascertained, but we confirmed that this region was deleted in all affected males, but not in the unaffected dogs. Quantitative polymerase chain reaction confirmed all three affected males were hemizygous for the mutant X chromosome, while the wildtype chromosome was observed in the unaffected male littermate. The female littermate and the dam were both heterozygous for the mutant chromosome. Forty-four Miniature Poodles from the general population were screened for the mutation and were homozygous for the wildtype chromosome. The finding represents a naturally-occurring mutation causing dystrophin-deficient muscular dystrophy in the dog. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.