Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 182331 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2017

Species-specific name: Spongy degeneration with cerebellar ataxia 2

Species-specific symbol: SDCA2

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 a genetic variant in the ATP1B2 gene. Other phenotypically related ataxias in dogs may also be caused by variants in the CAPN1, GRM1, ITPR1, KCNJ10, RAB24, SEL1L, SNX14, and SPTBN2 genes. In Belgian Shepherds, and especially in the Malinois variety, several genetically distinct forms of ataxia may occur. Apart from the ATP1B2-related SDCA2 described in this entry, the KCNJ10-related SDCA1 also occurs in this breed and leads to very similar clinical signs.

Mapping: Mauri et al. (2017) investigated a single family of Belgian Shepherd dogs (Malinois variety) consisting of both parents and a complete litter with 11 offspring to map the causative locus. Four out of the 11 puppies were affected by SDCA2. Using a combined linkage and homozygosity mapping approach the authors mapped the disease causing variant to Chr5:29,906,132–40,470,236 (CanFam 3.1 assembly).

Molecular basis: By whole-genome sequencing a single SDCA2 affected Belgian Shepherd, and comparing the data with genome sequences from 146 control canids, Mauri et al. (2017) identified a 227 bp SINE insertion into exon 2 of the ATP1B2 gene in the affected dog. The variant was described as XM_546597.5:ATP1B2:c.130_131insLT796559.1:g.50_276 or CanFam3.1:Chr5:32,551,064_32,551,065insLT796559.1:g.50_276. The SINE insertion was homozygous in 5 affected dogs. It did not occur in homozygous state in 258 control Belgian Shepherds. The variant was absent from 503 dogs of diverse other breeds. At the time of the canine study, there were no reports about human patients with ATP1B2 variants available. However, an Atp1b2 knockout mouse model displayed also a progressive motor impairment and spongy degeneration of the brain. Mauri et al. (2017) investigated the molecular consequences of the SINE insertion. Using skin RNA from one case, the authors detected at least three different aberrant splice isoforms. The epxressed transcripts all maintained the original reading frame. However, as several codons were altered in each of these isoforms, a loss of ATP1B2 function seems likely.

Clinical features: The primary clinical sign consisted of a loss of coordination and generalized ataxic gait starting at 4 weeks of age. SDCA2 affected dogs also had seizures, showed pacing and circling and developed central blindness. Due to the rapid progression of the neurological signs, most puppies were euthanized at 6 weeks of age. One affected puppy died at 6.5 weeks of age during a seizure (Mauri et al. 2017).

Pathology: "Histopathological changes ... were characterized by bilateral-symmetric vacuolation of the neuropil, targeting the cerebellar nuclei; the ventral horn gray matter of the spinal cord, in particular at the level of the cervical intumescence; and the brain stem. In the spinal cord, vacuolation was associated with neuronal necrosis and severe gliosis. Additionally, in the puppy MA162, neuronal necrosis and diffuse presence of hypertrophic astrocytes with vesicular nuclei, reminiscent of Alzheimer type II cells, were observed in the hippocampus, caudate nucleus, and diffusely in the cortex. Histopathological eye abnormalities were not noticed." (Mauri et al. 2017)

Breed: Belgian Shepherd Dog (Dog) (VBO_0200144).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: