title: Genome sequencing reveals a splice donor site mutation in the SNX14 gene associated with a novel cerebellar cortical degeneration in the Hungarian Vizsla dog breed.
abstract: Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions. There have been no previous reports of CCD in Hungarian Vizslas.
  
  
  
  Two full-sibling Hungarian Vizsla puppies from a litter of nine presented with a history of progressive ataxia, starting around three months of age. Clinical signs included marked hypermetric and dysmetric ataxia, truncal sway, intention tremors and absent menace responses, with positional horizontal nystagmus in one dog. Routine diagnostic investigations were unremarkable, and magnetic resonance imaging performed in one dog revealed mild craniodorsal cerebellar sulci widening, supportive of cerebellar atrophy. Owners of both dogs elected for euthanasia shortly after the onset of signs. Histopathological examination revealed primary Purkinje neuron loss consistent with CCD. Whole genome sequencing was used to successfully identify a disease-associated splice donor site variant in the sorting nexin 14 gene (SNX14) as a strong causative candidate. An altered SNX14 splicing pattern for a CCD case was demonstrated by RNA analysis, and no SNX14 protein could be detected in CCD case cerebellum by western blotting. SNX14 is involved in maintaining normal neuronal excitability and synaptic transmission, and a mutation has recently been found to cause autosomal recessive cerebellar ataxia and intellectual disability syndrome in humans. Genetic screening of 133 unaffected Hungarian Vizslas revealed the presence of three heterozygotes, supporting the presence of carriers in the wider population.
  
  
  
  This is the first report of CCD in Hungarian Vizsla dogs and identifies a highly associated splice donor site mutation in SNX14, with an autosomal recessive mode of inheritance suspected.
authors: Department of Clinical Science and Services, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, AL9 7TA, UK. jfenn@rvc.ac.uk.
authors: Joe
authors: 0000-0001-7851-670X
authors: J
authors: Fenn
authors: Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK.
authors: Mike
authors: M
authors: Boursnell
authors: Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK.
authors: Rebekkah J
authors: RJ
authors: Hitti
authors: Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK.
authors: Christopher A
authors: CA
authors: Jenkins
authors: Department of Pathology and Pathogen Biology, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, AL9 7TA, UK.
authors: Rebecca L
authors: RL
authors: Terry
authors: Department of Pathology and Pathogen Biology, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, AL9 7TA, UK.
authors: Simon L
authors: SL
authors: Priestnall
authors: Department of Clinical Science and Services, Royal Veterinary College, Hawkshead Lane, North Mymms, Hertfordshire, AL9 7TA, UK.
authors: Patrick J
authors: PJ
authors: Kenny
authors: Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK.
authors: Cathryn S
authors: CS
authors: Mellersh
authors: Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, Suffolk, CB8 7UU, UK.
authors: Oliver P
authors: OP
authors: Forman
mesh_terms: D000818:Animals; D002526:Cerebellar Diseases / Q000235:genetics / Q000662:veterinary*; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005260:Female; D023281:Genomics; D008297:Male; D009154:Mutation; D022821:RNA Splice Sites / Q000235:genetics*; D017421:Sequence Analysis; D058305:Sorting Nexins / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites; D058305:Sorting Nexins
keywords: Cerebellar abiotrophy; Cerebellar cortical degeneration; Genome sequencing; Hungarian Vizsla dog