Ataxia, spinocerebellar (ITPR1-related)

Gene: ITPR1

Transmission: Autosomal recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutation: Insertion, ITPR1 gene (microsatellite repeat variation): GAA expanded repeat in intron35-36, Chr.20.

Medical system: Neurologic

Breed: Spinone Italiano

Age of onset of symptoms: 4 months

An autosomal recessive hereditary neurodegenerative disease has been recognized in the Italian Spinone dog breed for more than 30 years.  Affected puppies begin to show clinical signs as early as four months of age, including an unsteady gait, exaggerated movements (hypermetria), trunk sway, and absence of the threat reflex. These deficits progressively worsen and culminate in an inability to stand or walk, often leading to euthanasia before one year of age.

Molecular studies identified an expanded microsatellite repeat within an intron of the ITPR1 gene as being present in two copies in affected animals and being present in one copy in non-affected but obligate carrier animals.  Microsatellite sites are normal but relatively unstable genetic elements found within the genome, and their instability can be the cause of genetic diseases.  The wild type (normal) microsatellite in the ITPR1 gene of the Italian Sinone consists of 7 to 22 copies of a GAA repeat, while the mutant microsatellite consists of an expansion of the GAA repeat to 300 to 650 copies.  Gene expression studies in tissues taken from affected dogs showed reduced but not absent expression of the ITPR1 gene in the Purkinje cells of the cerebellum. The ITPR1 gene codes for an intracellular calcium channel protein that is a receptor for IP3 signalling and is involved in regulating cellular Ca2+ levels.  Proper expression of ITPR1 is particularly important in the cerebellum, and disrupted expression is one cause of spinocerebellar ataxia seen in humans.

The current frequency of the ITPR1 mutation within the Italian Spinone population has not been reported, but the availability of a DNA test for the mutation and an earlier linkage test have allowed breeders to drastically reduce the incidence of the disease by selective breeding.  Whether or not the disease can be definitely eliminated is another question, as the periodic expansion of normal microsatellite sites is a known cause of re-emergence of similar ataxia diseases in humans.

References:

OMIA link: [2097-9615]

Cocostîrc V, Paștiu AI, Pusta DL. (2023) An overview of canine inherited neurological disorders with known causal variants. Animals (Basel) 13:3568.  [38003185]

Stee K, Van Poucke M, Lowrie M, et al. (2023) Phenotypic and genetic aspects of hereditary ataxia in dogs. J Vet Intern Med 37:1306-1322. [pm/37341581]

Forman OP, De Risio L, Matiasek K, et al. (2015) Spinocerebellar ataxia in the Italian Spinone dog is associated with an intronic GAA repeat expansion in ITPR1. Mamm Genome 26:108-17. [pm/25354648]

Wheeler S, Rusbridge C. (1996) Neurological syndrome in Italian spinones. Vet Rec. 138:216.  [pm/8686161]

With contributions by: Sara Michelle Goulet and Anne Bohan Lu, Class of 2030, Faculty of Veterinary Medicine, University of Montreal.  (Translation: DWS).