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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0433-y) contains supplementary material, which is available to authorized users.

Characterisation of canine KCNIP4: A novel gene for cerebellar ataxia identified by whole-genome sequencing two affected Norwegian Buhund dogs

“…In the present study we used whole genome sequencing to identify the causal mutation for a recently characterised cerebellar ataxia in the Norwegian Buhund dog breed [18]. Whole genome sequencing of single cases of ataxia has recently been used to successfully identify mutations causing cerebellar cortical degeneration (CCD) in the Hungarian Vizsla and spinocerebellar ataxia in Russell Group Terriers [5,17]. Taken together this suggests that cerebellar ataxias in the dog are particularly amenable to this approach for the identification of causal mutations.…”

“…Multiple examples of hereditary ataxia have been described in purebred dogs [3][4][5][6][7][8][9]. Although the specific diseases are often rare, and the genetic mutations can be breed-specific, hereditary ataxia is a key cause of movement disorders in dogs.…”

“…Canine hereditary ataxia is typically inherited in an autosomal recessive manner, and disease-causing variants have been identified for some breeds [3][4][5][6][7][8][9][10][11][12]. Some of the genes implicated in canine ataxia had not previously been associated with disease in humans [12][13][14][15], whereas other forms of canine ataxia are caused by variants within the same genes that are associated with well characterised forms of human ataxia [4][5][6]16]. Canine hereditary ataxia is a naturally occurring disease model and research into the genetics of ataxia in purebred dogs can help improve the understanding of the underlying molecular mechanisms of human disease.…”

“…Genome-wide association studies (GWAS) have been used to identify the causal mutations for CCD in Finnish Hounds (SEL1L, targeted degradation of misfolded or unassembled peptides), and Old English Sheepdogs and Gordon Setters (RAB24, which has a role in autophagy); and spinocerebellar ataxia in Russell Terrier Group dogs (CAPN1, which encodes μ-calpain, a subunit of calcium dependent cysteine protease) [13][14][15]. Whole genome sequencing of single cases of ataxia has been used more recently to successfully identify causal variants for CCD in the Hungarian Vizsla (SNX14, which has a role in the maintenance of neuronal excitability and synaptic transmission, and is associated with cerebellar ataxia in humans) [5] and spinocerebellar ataxia in Russell Group Terriers (KCNJ10, a potassium channel gene) [17]. Both of these studies used control genomes, and predicted effect on the protein sequence, to filter common benign variants, and then identified variants within candidate genes for genotyping in additional dogs.…”

Exclusion of known gene loci for cerebellar abiotrophy in the Australian Working Kelpie

“…Eleven sequence variants have been previously identified as causative for CA in 15 dog breeds (Beagle, Belgian Shepherd Malinois, Coton de Tulear, Eurasier, Finnish Hound, Hungarian Vizsla, Italian Spinone, Lagotto Romagnolo, Old English Sheepdog, Gordon Setter, Parson Russell Terrier, Jack Russell Terrier, Russell Terrier, Smooth‐haired Fox Terrier, and Toy Fox Terrier) . For the current study, we examined the described variants for segregation in AWK (Table ).…”