OMIA 000263-9615 : Degenerative myelopathy in Canis lupus familiaris
By conducting a GWAS on 15 affected and 69 control German Shepherd dogs, each genotyped with the Affymetrix v2 canine SNP chip (Yielding 48,415 SNPs for the analysis), Tsai et al. (2012) highlighted a 1.615Mb region on chromosome CFA31 (the same as that highlighted by Awano et al., 2009), which contains the SOD1 gene, mutations in which had already been shown to be causal (see Molecular basis section).Molecular basis: The first likely causative variant described is a G to A transition (c.118G>A; p.E40K) in exon 2 of SOD1. All affected dogs tested were homozygous mutant. However, some homozygous mutant dogs had no signs of degenerative myelopathy, which suggests incomplete penetrance or other causative loci (Awano et al., 2009). The mutation is hypothesized to lead to SOD1 aggregation, as cytoplasmic inclusions in affected dogs stain with anti-SOD1 antibodies (Awano et al., 2009).
A second causal mutation (c.52A>T; p.Thr18Ser) in the same gene, in a Bernese Mountain Dog, was reported by Wininger et al. (2011).
Having genotyped 408 Bernese Mountains dogs for both the above mutations, Pfahler et al. (2014) reported that "The c.118G>A mutation was heterozygous in 188 (46.1%) and homozygous in 27 (6.6%) BMD (Table S2). The c.52A>T mutation was heterozygous in 65 (15.9%) and homozygous in two (0.5%) dogs. Twenty-two of the animals had both SOD1 mutations heterozygous (5.4%). The haplotype analysis for all BMD revealed no haplotype with both mutated alleles on a single chromosome (Figs S1 and S2). Therefore, these 22 dogs are likely to be compound heterozygous for the SOD1 haplotypes AA and TG." One of the 22 compound heterozygotes showed clinical signs of degenerative myelopathy. Summarising all available evidence, Pfahler et al. (2014) concluded that "compound heterozygosity [for the two mutations] may confer a similar risk to DM like the c.118G>A homozygous mutation".
Ivansson et al. (2016) reported "that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation"
Mandrioli et al. (2021) reported that "three [affected Hovawart] dogs were homozygous for the c.118A allele, but none had the SP110 'risk' haplotype, suggesting a weak association of SP110 with the onset of DM in this breed. Our data suggest that the Hovawart breed is predisposed to the SOD1:c.118G>A mutation, which is associated with the development of DM."Clinical features: Most dogs are at least 8 years of age at the onset of clinical signs, which include hyporeflexia, upper motor neuron proprioceptive spasticity and ataxia in the pelvic limbs. These progress to paraplegia and eventually flaccid tetraparesis (Awano et al., 2009). There is no effective treatment. Pathology: Histopathologic examination of the spinal cord is necessary for definitive diagnosis. Noninflammatory axonal and myelin degeneration is present at all levels of the spinal cord, being most severe in the dorsal lateral funiculus within the middle to caudal thoracic region. Segmental axonal and myelin degeneration, endoneurial fibrosis, hypomyelinated fibers and secondary demyelination are present in peripheral nerves. Axon cylinder vacuolization is characteristic (Coates et al., 2010). Prevalence: In an extensive project, Zeng et al. (2014) genotyped 33,747 dogs representing 222 breeds for both known mutant alleles, namely c.52T and c.118A. They concluded that "the SOD1:c.118A allele is widespread and common among privately owned dogs whereas the SOD1:c.52T allele is rare and appears to be limited to Bernese Mountain Dogs." Full details are available in the paper.
Mizukami et al. (2016) reported the frequency of the c.118A allele as 0.008 in 500 Border collies in Japan.
Regarding the insertion reported by Turba et al. (2107), these authors reported that "The allele containing the insertion was highly prevalent in Hovawart dogs, accounting for the 26.6% of allele frequency. The insertion was also found in other unrelated breeds such as Rough Collies and Standard Poodles."
Santos et al. (2020) genotyped 97 German Shepherd dogs for the SOD1:c.118G>A mutation using a PCR/RFLP test. The dogs were located in Brazil and had no clinical signs of degenerative myelopathy at the time of sampling. They “observed genotype frequencies (with 95% confidence interval) of: 0.758 (0.672-0.844), 0.242 (0.156-0.328) and 0.000 (0.000-0.000) for "GG", "AG" and "AA" genotypes, respectively.”Control: Due to the high frequency of the causative mutation in Boxers and Pembroke Welsh Corgis, in these breeds it is not practical to exclude carriers from breeding, so it is recommended that carriers be bred to noncarriers. Breeding of affected dogs of any breed should be avoided. Genetic testing: Investigating the "many discordant findings between the parental and the offspring genotypes found by different laboratories" in testing for the c.118G>A variant, Turba et al. (2017) discovered "An insertion of 54 nucleotides [in the SOD1 gene] composed of a poly-T stretch and 15 nucleotides containing the duplication of the exon 2-intron 2 junction was . . . responsible for the partial mismatch of the reverse primer used for a direct sequencing assay. The mismatch hampered the amplification of the corresponding allele and caused an evident drop-out effect. The insertion is in complete linkage disequilibrium with the c.118G allele."
Santos et al. (2020) identified “a deletion of one “T” in the position 26540247 described as ENSCAFG00000008859:g.26540247del … located in the intron 1 of the SOD1 gene. … Although the role of the ENSCAFG00000008859:g.26540247del on structure and expression of SOD1 (and consequently its relationship with CDM) was not investigated in this study, its location does not suggest that it can influence the expression of the studied disease.” However, this variant prevented in a small number of dogs adequate genotyping of the SOD1:c.118G>A in the PCR-RFLP test used in this study.Breeds: American Eskimo dog, Bernese Mountain dog, Boxer, Cardigan Welsh Corgi, Chesapeake Bay Retriever, German Shepherd Dog, Golden Retriever, Hovawart, Kerry Blue Terrier, Miniature Poodle, Pembroke Welsh Corgi, Pug, Rhodesian Ridgeback, Siberian Husky, Soft Coated Wheaten Terrier, Standard Poodle, Wirehaired Fox Terrier. Associated genes:
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|SOD1||superoxide dismutase 1, soluble||Canis lupus familiaris||31||NC_051835.1 (26654922..26662986)||SOD1||Homologene, Ensembl, NCBI gene|
|SP110||SP110 nuclear body protein||Canis lupus familiaris||25||NC_051829.1 (42715740..42674227)||SP110||Homologene, Ensembl, NCBI gene|
By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.
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.
|Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Year Published||PubMed ID(s)||Acknowledgements|
|Bernese Mountain dog||Degenerative myelopathy||SOD1||missense||c.52A>T||p.T18S||2011||21628865|
|Boxer Chesapeake Bay Retriever German Shepherd Dog Hovawart Pembroke Welsh Corgi Rhodesian Ridgeback||Degenerative myelopathy||SOD1||missense||CanFam2.0||31||c.118G>A||p.E40K||2009||19188595|
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.
|2021||Mandrioli, L., Gandini, G., Gentilini, F., Chiocchetti, R., Turba, M.E., Avallone, G., Pellegrino, V., Menchetti, M., Kobatake, Y., Kamishina, H., Cantile, C. :|
|Degenerative Myelopathy in Hovawart Dogs: Molecular Characterization, Pathological Features and Accumulation of Mutant Superoxide Dismutase 1 Protein. J Comp Pathol 182:37-42, 2021. Pubmed reference: 33494906. DOI: 10.1016/j.jcpa.2020.11.006.|
|2020||Draper, A.C.E., Wilson, Z., Maile, C., Faccenda, D., Campanella, M., Piercy, R.J. :|
|Species-specific consequences of an E40K missense mutation in superoxide dismutase 1 (SOD1). FASEB J 34:458-473, 2020. Pubmed reference: 31914665. DOI: 10.1096/fj.201901455R.|
|Kimura, S., Kamatari, Y.O., Kuwahara, Y., Hara, H., Yamato, O., Maeda, S., Kamishina, H., Honda, R. :|
|Canine SOD1 harboring E40K or T18S mutations promotes protein aggregation without reducing the global structural stability. PeerJ 8:e9512, 2020. Pubmed reference: 32742795. DOI: 10.7717/peerj.9512.|
|Santos, C.R.O., Gouveia, J.J.S., Gouveia, G.V., Bezerra, F.C.M., Nogueira, J.F., Baraúna Júnior, D. :|
|Molecular screening for the mutation associated with canine degenerative myelopathy (SOD1:c.118G > A) in German Shepherd dogs in Brazil. PLoS One 15:e0242347, 2020. Pubmed reference: 33196688. DOI: 10.1371/journal.pone.0242347.|
|Story, B.D., Miller, M.E., Bradbury, A.M., Million, E.D., Duan, D., Taghian, T., Faissler, D., Fernau, D., Beecy, S.J., Gray-Edwards, H.L. :|
|Canine models of inherited musculoskeletal and neurodegenerative diseases. Front Vet Sci 7:80, 2020. Pubmed reference: 32219101. DOI: 10.3389/fvets.2020.00080.|
|2017||Kobatake, Y., Sakai, H., Tsukui, T., Yamato, O., Kohyama, M., Sasaki, J., Kato, S., Urushitani, M., Maeda, S., Kamishina, H. :|
|Localization of a mutant SOD1 protein in E40K-heterozygous dogs: Implications for non-cell-autonomous pathogenesis of degenerative myelopathy. J Neurol Sci 372:369-378, 2017. Pubmed reference: 27838005. DOI: 10.1016/j.jns.2016.10.034.|
|Kohyama, M., Kitagawa, M., Kamishina, H., Kobatake, Y., Yabuki, A., Sawa, M., Kakita, S., Yamato, O. :|
|Degenerative myelopathy in the Collie breed: a retrospective immunohistochemical analysis of superoxide dismutase 1 in an affected Rough Collie, and a molecular epidemiological survey of the SOD1: c.118G>A mutation in Japan. J Vet Med Sci 79:375-379, 2017. Pubmed reference: 27941298. DOI: 10.1292/jvms.16-0391.|
|Turba, M.E., Loechel, R., Rombolà, E., Gandini, G., Gentilini, F. :|
|Evidence of a genomic insertion in intron 2 of SOD1 causing allelic drop-out during routine diagnostic testing for canine degenerative myelopathy. Anim Genet 48:365-368, 2017. Pubmed reference: 27917507. DOI: 10.1111/age.12525.|
|2016||Ivansson, E.L., Megquier, K., Kozyrev, S.V., Murén, E., Körberg, I.B., Swofford, R., Koltookian, M., Tonomura, N., Zeng, R., Kolicheski, A.L., Hansen, L., Katz, M.L., Johnson, G.C., Johnson, G.S., Coates, J.R., Lindblad-Toh, K. :|
|Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy. Proc Natl Acad Sci U S A 113:E3091-100, 2016. Pubmed reference: 27185954. DOI: 10.1073/pnas.1600084113.|
|Mizukami, K., Yabuki, A., Kohyama, M., Kushida, K., Rahman, M.M., Uddin, M.M., Sawa, M., Yamato, O. :|
|Molecular prevalence of multiple genetic disorders in Border collies in Japan and recommendations for genetic counselling. Vet J 214:21-3, 2016. Pubmed reference: 27387721. DOI: 10.1016/j.tvjl.2016.05.004.|
|Nardone, R., Höller, Y., Taylor, A.C., Lochner, P., Tezzon, F., Golaszewski, S., Brigo, F., Trinka, E. :|
|Canine degenerative myelopathy: a model of human amyotrophic lateral sclerosis. Zoology (Jena) 119:64-73, 2016. Pubmed reference: 26432396. DOI: 10.1016/j.zool.2015.09.003.|
|2014||Holder, A.L., Price, J.A., Adams, J.P., Volk, H.A., Catchpole, B. :|
|A retrospective study of the prevalence of the canine degenerative myelopathy associated superoxide dismutase 1 mutation (SOD1:c.118G > A) in a referral population of German Shepherd dogs from the UK. Canine Genet Epidemiol 1:10, 2014. Pubmed reference: 26401327. DOI: 10.1186/2052-6687-1-10.|
|Lovett, M.C., Coates, J.R., Shu, Y., Oglesbee, M.J., Fenner, W., Moore, S.A. :|
|Quantitative assessment of hsp70, IL-1β and TNF-α in the spinal cord of dogs with E40K SOD1-associated degenerative myelopathy. Vet J :, 2014. Pubmed reference: 24662024. DOI: 10.1016/j.tvjl.2014.03.003.|
|Pfahler, S., Bachmann, N., Fechler, C., Lempp, C., Baumgärtner, W., Distl, O. :|
|Degenerative myelopathy in a SOD1 compound heterozygous Bernese mountain dog. Anim Genet 45:309-10, 2014. Pubmed reference: 24450472. DOI: 10.1111/age.12118.|
|Zeng, R., Coates, J.R., Johnson, G.C., Hansen, L., Awano, T., Kolicheski, A., Ivansson, E., Perloski, M., Lindblad-Toh, K., O'Brien, D.P., Guo, J., Katz, M.L., Johnson, G.S. :|
|Breed distribution of SOD1 alleles previously associated with canine degenerative myelopathy. J Vet Intern Med 28:515-21, 2014. Pubmed reference: 24524809. DOI: 10.1111/jvim.12317.|
|2013||Broeckx, B.J., Coopman, F., Verhoeven, G.E., Van Haeringen, W., van de Goor, L., Bosmans, T., Gielen, I., Saunders, J.H., Soetaert, S.S., Van Bree, H., Van Neste, C., Van Nieuwerburgh, F., Van Ryssen, B., Verelst, E., Van Steendam, K., Deforce, D. :|
|The prevalence of nine genetic disorders in a dog population from Belgium, the Netherlands and Germany. PLoS One 8:e74811, 2013. Pubmed reference: 24069350. DOI: 10.1371/journal.pone.0074811.|
|Chang, H.S., Kamishina, H., Mizukami, K., Momoi, Y., Katayama, M., Rahman, M.M., Uddin, M.M., Yabuki, A., Kohyama, M., Yamato, O. :|
|Genotyping assays for the canine degenerative myelopathy-associated c.118G>A (p.E40K) mutation of the SOD1 gene using conventional and real-time PCR methods: a high prevalence in the Pembroke Welsh Corgi breed in Japan. J Vet Med Sci 75:795-8, 2013. Pubmed reference: 23328634.|
|Crisp, M.J., Beckett, J., Coates, J.R., Miller, T.M. :|
|Canine degenerative myelopathy: biochemical characterization of superoxide dismutase 1 in the first naturally occurring non-human amyotrophic lateral sclerosis model. Exp Neurol 248:1-9, 2013. Pubmed reference: 23707216. DOI: 10.1016/j.expneurol.2013.05.009.|
|Ogawa, M., Uchida, K., Yamato, O., Inaba, M., Uddin, M.M., Nakayama, H. :|
|Neuronal Loss and Decreased GLT-1 Expression Observed in the Spinal Cord of Pembroke Welsh Corgi Dogs With Canine Degenerative Myelopathy. Vet Pathol :, 2013. Pubmed reference: 23839236. DOI: 10.1177/0300985813495899.|
|Shafie, I.N., McLaughlin, M., Burchmore, R., Lim, M.A., Montague, P., Johnston, P.E., Penderis, J., Anderson, T.J. :|
|The chaperone protein clusterin may serve as a cerebrospinal fluid biomarker for chronic spinal cord disorders in the dog. Cell Stress Chaperones :, 2013. Pubmed reference: 23990410. DOI: 10.1007/s12192-013-0457-4.|
|2012||Shelton, G.D., Johnson, G.C., O'Brien, D.P., Katz, M.L., Pesayco, J.P., Chang, B.J., Mizisin, A.P., Coates, J.R. :|
|Degenerative myelopathy associated with a missense mutation in the superoxide dismutase 1 (SOD1) gene progresses to peripheral neuropathy in Pembroke Welsh corgis and boxers. J Neurol Sci 318:55-64, 2012. Pubmed reference: 22542607. DOI: 10.1016/j.jns.2012.04.003.|
|Tsai, K.L., Noorai, R.E., Starr-Moss, A.N., Quignon, P., Rinz, C.J., Ostrander, E.A., Steiner, J.M., Murphy, K.E., Clark, L.A. :|
|Genome-wide association studies for multiple diseases of the German Shepherd Dog. Mamm Genome 23:203-11, 2012. Pubmed reference: 22105877. DOI: 10.1007/s00335-011-9376-9.|
|2011||Ogawa, M., Uchida, K., Park, E.S., Kamishina, H., Sasaki, J., Chang, H.S., Yamato, O., Nakayama, H. :|
|Immunohistochemical observation of canine degenerative myelopathy in two Pembroke Welsh Corgi dogs. J Vet Med Sci 73:1275-9, 2011. Pubmed reference: 21628865.|
|2010||Coates, JR., Wininger, FA. :|
|Canine degenerative myelopathy. Vet Clin North Am Small Anim Pract 40:929-50, 2010. Pubmed reference: 20732599. DOI: 10.1016/j.cvsm.2010.05.001.|
|2009||Awano, T., Johnson, GS., Wade, CM., Katz, ML., Johnson, GC., Taylor, JF., Perloski, M., Biagi, T., Baranowska, I., Long, S., March, PA., Olby, NJ., Shelton, GD., Khan, S., O'Brien, DP., Lindblad-Toh, K., Coates, JR. :|
|Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 106:2794-9, 2009. Pubmed reference: 19188595. DOI: 10.1073/pnas.0812297106.|
|Miller, AD., Barber, R., Porter, BF., Peters, RM., Kent, M., Platt, SR., Schatzberg, SJ. :|
|Degenerative myelopathy in two Boxer dogs. Vet Pathol 46:684-7, 2009. Pubmed reference: 19276068. DOI: 10.1354/vp.08-VP-0270-M-BC.|
|2008||Coates, JR., March, PA., Oglesbee, M., Ruaux, CG., Olby, NJ., Berghaus, RD., O'Brien, DP., Keating, JH., Johnson, GS., Williams, DA. :|
|Clinical characterization of a familial degenerative myelopathy in Pembroke Welsh Corgi dogs. J Vet Intern Med 21:1323-31, 2008. Pubmed reference: 18196743.|
|1994||Barclay, K.B., Haines, D.M. :|
|Immunohistochemical Evidence for Immunoglobulin and Complement Deposition in Spinal Cord Lesions in Degenerative Myelopathy in German Shepherd Dogs Canadian Journal of Veterinary Research - Revue Canadienne de Recherche Veterinaire 58:20-24, 1994. Pubmed reference: 8143248.|
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