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

BMC Genetics

Research Article

Joe Fenn¹  Patrick J. Kenny¹  Simon L. Priestnall²  Rebecca L. Terry²  Christopher A. Jenkins³  Cathryn S. Mellersh³  Mike Boursnell³  Rebekkah J. Hitti³  Oliver P. Forman³ 

[1]Department of Clinical Science and Services, Royal Veterinary College, Hawkshead Lane, North Mymms, AL9 7TA, Hertfordshire, UK

[2]Department of Pathology and Pathogen Biology, Royal Veterinary College, Hawkshead Lane, North Mymms, AL9 7TA, Hertfordshire, UK

[3]Kennel Club Genetics Centre, Animal Health Trust, Kentford, Newmarket, CB8 7UU, Suffolk, UK

关键词: Cerebellar cortical degeneration;    Cerebellar abiotrophy;    Hungarian Vizsla dog;    Genome sequencing;   

DOI  :  10.1186/s12863-016-0433-y

 received in 2016-03-01, accepted in 2016-08-24,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundCerebellar 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.ResultsTwo 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.ConclusionsThis 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.

【 授权许可】

CC BY   
© The Author(s). 2016