OMIA 000263-9615 : Degenerative myelopathy in Canis lupus familiaris

See the equivalent entry at NCBI

Possible human homologue (MIM number): 105400

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key mutation known: yes

Year key mutation first reported: 2009

Species-specific name: Canine degenerative myelopathy

Species-specific symbol: DM

Species-specific description: This is an adult onset degeneration of the spinal cord that progresses to paraplegia and tetraparesis. There is no successful treatment. A genetic test is available.

Mapping: By conducting a GWAS on 38 affected and 17 control Pembroke Welsh corgis, each genotyped with the Affymetrix Canine Genome 2.0 Array (yielding 49,663 SNPs for analysis), Awano et al. (2009) highlighted a region of chromosome CFA31 that contains the comparative candidate gene, SOD1.

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 causative mutation 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"

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."

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 carriers of other breeds, or affected dogs of any breed, should be avoided.

Genetic testing: A test is available.

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."

Breeds: American Eskimo dog, Bernese Mountain dog, Boxer, Cardigan Welsh Corgi, Chesapeake Bay Retriever, German shepherd, Golden Retriever, 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_006613.3 (26540291..26544212) SOD1 Homologene, Ensembl, NCBI gene
SP110 SP110 nuclear body protein Canis lupus familiaris 25 NC_006607.3 (42459098..42418565) SP110 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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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 Pembroke Welsh Corgi Rhodesian Ridgeback Degenerative myelopathy SOD1 missense CanFam3.1 31 g.26540342G>A c.100G>A p.E34K rs853026434 2009 19188595 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

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.
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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