OMIA:002097-9615 : Ataxia, spinocerebellar, ITPR1-related in Canis lupus familiaris (dog)
Categories: Nervous system phene
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2015
Species-specific name: Spinocerebellar ataxia
Species-specific symbol: SCAIS
Species-specific description: Ataxia is characterized by uncoordinated movements and represents a relatively non-specific clinical sign. This entry describes an ataxia form that is caused by genetic variants in the ITPR1 gene. Other phenotypically related ataxias in dogs may also be caused by variants in the ATP1B2, CAPN1, GRM1, KCNJ10, RAB24, SEL1L, SNX14, and SPTBN2 genes. Thus locus heterogeneity for this phenotype must be considered.
Mapping: Forman et al. (2015) genotyped microsatellite markers in 6 cases and 6 controls and detected homzygosity in the cases for two markers on chomosome 20. An extended linkage analyses using 13 cases and 47 controls gave a LOD score of 4.41 for the marker C20.374 on chromosome 20. Fine mapping defined a critical interval at chr20:15,601,140–17,116,778 based on the genomic coordinates of the CanFam2 assembly.
Molecular basis: Forman et al. (2015) identified an expanded GAA-repeat in intron 35 of the ITPR1 gene in affected dogs. The wildtype sequence contains 8 GAA repeats. The expanded disease-associated alleles carry an estimated 318-651 GAA repeats. Using immunohistochemistry Forman et al. (2015) observed reduced ITPR1 protein expression in Purkinje cells of the cerebellum and a distortion of the monoplanar orientation of the dendritic trees. "This is the first reported naturally occurring pathogenic intronic repeat expansion in a nonhuman species." (Forman et al. 2015).
Clinical features: "Clinical signs start to appear at four months of age and progress to a degree of dysfunction which leads to euthanasia of affected dogs at one year of age on average." ... "Neurological characteristics of SCAIS include a wide-based stance, spinocerebellar ataxia characterised by thoracic limb hypermetria (hyperextension), pelvic limb hyperflexion, truncal swaying, impaired balance, pendular nystagmus and absent menace response bilaterally. The remainder of the neurological examination was within normal limits. As the disease progressed intentional head tremor was observed and balance impairment deteriorated to the point that the dogs were unable to stand up and ambulate at approximately 1 year of age." (Forman et al. 2015)
Pathology: "The overall size and volume ratios of ITPR1 mutant Italian Spinone cerebella as well as the lobule and folia formation, the diameters of the fissures and sulci and the area of the subarachnoid space were within a normal range. Cerebellocortical layers were sharply delineated, the Purkinje cells (PC) were correctly placed and the granule cell layer presented with normal density and glomerula formation." ... "In affected IS, the molecular layer exhibited some focal stellate cell hypercellularity." (Forman et al. 2015). Immunohistochemistry with an anti-ITPR1 antibody revealed "a distortion of the of monoplanar orientation of the dendritic trees. Instead of the two-dimensional arborisation in sagittal plane, the dendrites, now birch-broom-like, extended into the molecular layer towards the pial membrane. Thereby, secondary and tertiary dendrites and spiny branchlets left the stem at a moderately steep angle (Fig. 6d). Both reduced ITPR1 expression and the defective planar orientation of immunopositive cells involved all lobules and functional subfields of the affected cerebella with a mild emphasis on the spinocerebellar parts of the vermis." (Forman et al. 2015)
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|ITPR1||inositol 1,4,5-trisphosphate receptor, type 1||Canis lupus familiaris||20||NC_051824.1 (13108309..12789247)||ITPR1||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|754||Italian Spinone||Ataxia, spinocerebellar||ITPR1||complex rearrangement||Naturally occurring variant||20||Forman et al. (2015) identified an expanded GAA-repeat in intron 35 of the ITPR1 gene in affected dogs. The wildtype sequence contains 8 GAA repeats. The expanded disease-associated alleles carry an estimated 318-651 GAA repeats.||2015||25354648|
Cite this entry
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2023||Stee, K., Van Poucke, M., Lowrie, M., Van Ham, L., Peelman, L., Olby, N., Bhatti, S.F.M. :|
|Phenotypic and genetic aspects of hereditary ataxia in dogs. J Vet Intern Med :, 2023. Pubmed reference: 37341581 . DOI: 10.1111/jvim.16742.|
|2015||Forman, O.P., De Risio, L., Matiasek, K., Platt, S., Mellersh, C. :|
|Spinocerebellar ataxia in the Italian Spinone dog is associated with an intronic GAA repeat expansion in ITPR1. Mamm Genome 26:108-17, 2015. Pubmed reference: 25354648 . DOI: 10.1007/s00335-014-9547-6.|
- Created by Tosso Leeb on 02 Mar 2017
- Changed by Tosso Leeb on 02 Mar 2017
- Changed by Tosso Leeb on 07 Jul 2017