OMIA:002367-9615 : Ataxia, cerebellar, SELENOP-related in Canis lupus familiaris (dog) |
Categories: Nervous system phene
Links to possible relevant human trait(s) and/or gene(s) in OMIM: 601484 (gene)
Single-gene trait/disorder: yes
Mode of inheritance: Autosomal recessive
Disease-related: yes
Key variant known: yes
Year key variant first reported: 2021
Species-specific name: CNS atrophy with cerebellar ataxia
Species-specific symbol: CACA
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 SELENOP gene. Considerable genetic heterogeneity exists and variants in many other genes can lead to clinically similar phenotypes. In Belgian Shepherds, variants in KCNJ10 and ATP1B2 lead to clinically similar ataxia forms termed SDCA1 and SDCA2.
Mapping: Using parametric linkage and homozygosity mapping in a single family with 4 affected and 4 non-affected puppies, Christen et al. (2021) mapped the CACA locus to a critical interval of 52 Mb on chromosome 4 (Chr4:28,708,283-80;608,758, CanFam 3.1 assembly).
Molecular basis: Whole genome sequencing of an affected dog revealed a homozygous ~17 kb deletion spanning the entire protein coding region of the SELENOP gene [also called SEPP1]. The exact genomic designation of the deletion is Chr4:66,946,539_66,963,863del17,325 (CanFam 3.1). The deletion was private to the sequenced dog and absent from 735 control genomes of genetically diverse dogs and wolves. Genotypes at the deletion cosegregated with the CACA phenotype in the studied family. Genotyping additional archived ataxia cases revealed another ataxic dog that carried the SELNOP deletion in homozygous state (Christen et al. 2021). The SELENOP gene "encodes selenoprotein P, which functions in storing and transporting selenium. Selenoprotein P is the only known protein in vertebrates containing multiple selenocysteine residues. It is primarily synthesized in the liver and secreted into the blood stream. Incorporation of selenium into selenoprotein P prevents the toxic effects of free selenium and the majority of plasma selenium is bound in selenoprotein P. Studies in Selenop-/- knockout mice demonstrated that selenoprotein P is required for the transport of selenium into the brain and other organs." ... "Selenoprotein P delivery through the blood-brain barrier is mediated by the low density lipoprotein receptor-related protein 8 (LRP8). Selenoprotein P can be degraded via the lysosomal pathway to provide selenium for the de novo synthesis of other selenoproteins in the brain." ... "Selenium is required in several enzymes such as the glutathione peroxidases and thioredoxin reductases that protect cells from oxidative stress." (Christen et al. 2021). Christen et al. (2021) determined that the total selenium concentration in the blood of homozygous mutant CACA-affected puppies was reduced to approximately 30% of the value seen in wildtype dogs. Heterozygous carriers had approximately 70% of the normal selenium concentration in their blood.
Clinical features: The severity of the clinical phenotype is variable. The four affected dogs of the index family developed uncoordinated movements and intention tremor at two weeks of age. Due to the severity of their clinical signs, they were euthanized at 27 days of age. Another affected dog developed ataxia as a puppy, but remained in a relatively stable condition (with pronounced ataxia) and reached an age of 10 years (Christen et al. 2021).
Pathology: "During necropsy no gross lesions were detectable except for mild anemia. Histologically, all four animals showed similar lesions in brain and spinal cord to variable extent. In the cerebellum, all cortical layers were atrophic with depletion of Purkinje cells and granule cells. Neuroaxonal degeneration was present in midbrain, brain stem and spinal cord. Myelin content was severely diminished in the white matter of brain and spinal cord. Gliosis was evident in affected regions showing activation and increased numbers of astrocytes and microglial cells, respectively" (Christen et al. 2021).
Prevalence: At the time of the initial description, Christen et al. (2021) genotyped 631 non-affected Belgian Shepherds. They found 38 heterozygous carriers in this cohort, which corresponds to a carrier frequency of 6%.
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:
Symbol | Description | Species | Chr | Location | OMIA gene details page | Other Links |
---|---|---|---|---|---|---|
SEPP1 | selenoprotein P, plasma, 1 | Canis lupus familiaris | 4 | NC_051808.1 (67462747..67473870) | SEPP1 | Homologene, Ensembl , NCBI gene |
Variants
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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 | Year Published | PubMed ID(s) | Acknowledgements |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1334 | Belgian Shepherd Dog (Dog) | CNS atrophy with cerebellar ataxia | SEPP1 | deletion, gross (>20) | Naturally occurring variant | CanFam3.1 | 4 | g.66946539_66963863del | c.-6582_*516del | NM_001115118.1; ; 17325bp deletion includes the entire protein coding sequence of SELENOP (also called SEPP1) | 2021 | 34339417 |
Cite this entry
Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:002367-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70
References
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 | Cocostîrc, V., Paștiu, A.I., Pusta, D.L. : |
An overview of canine inherited neurological disorders with known causal variants. Animals (Basel) 13:3568, 2023. Pubmed reference: 38003185. DOI: 10.3390/ani13223568. | |
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 37:1306-1322, 2023. Pubmed reference: 37341581. DOI: 10.1111/jvim.16742. | |
2021 | Christen, M., Högler, S., Kleiter, M., Leschnik, M., Weber, C., Thaller, D., Jagannathan, V., Leeb, T. : |
Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs. PLoS Genet 17:e1009716, 2021. Pubmed reference: 34339417. DOI: 10.1371/journal.pgen.1009716. |
Edit History
- Created by Imke Tammen2 on 26 Jul 2021
- Changed by Tosso Leeb on 10 Aug 2021
- Changed by Imke Tammen2 on 11 Aug 2021
- Changed by Imke Tammen2 on 11 Sep 2024