Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 606658 , 117360 , 206700

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)

Breed: Italian Spinone.

Associated gene: