OMIA:001522-9615 : Oculoskeletal dysplasia 1 in Canis lupus familiaris
Categories: Skeleton phene (incl. short stature & teeth)
Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 154780 (trait) , 120270 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2010
Cross-species summary: This disorder has been renamed in OMIA on the basis of the review by Miyadera et al. (2012)
Species-specific symbol: osd1; drd1
Species-specific description: Oculoskeletal dysplasia is a collagen disorder characterized by short-limbed dwarfism, particularly of the forelimbs, and vitreous dysplasia with associated retinal detachment and cataracts. A genetic test is available.
History: This disorder was characterized in the Labrador retriever by Farnum et al (1992) and Carrig et al (1977).
Inheritance: Obligate heterozygotes do not have skeletal lesions but may exhibit mild ocular lesions (Goldstein et al., 2010).
Molecular basis: The likely causal variant in Labradors is an insertion of a guanine residue in exon 1 in the COL3 domain of COL9A3, causing an amino acid codon frameshift and a premature stop codon. Reduced RNA expression is found in affected retinas (Goldstein et al., 2010). It is currently thought that the causative mutation leads to collagen absence or deficiency in cartilage and ocular collagen, with a larger effect in vitreous and retinal tissue than in the limbs (Goldstein et al., 2010).
Stavinohova et al. (2019) reported a likely causal variant in Northern Inuit Dogs (NID) to be "a nonsense single nucleotide polymorphism [c.700C>T; p.Arg234Ter] in COL9A3".
Clinical features: Signs may be noticeable as early as 4 to 6 weeks of age (Carrig et al., 1997; Goldstein et al., 2010). Affected dogs have short-limbed dwarfism and vitreous dysplasia. Associated ophthalmic lesions include retinal detachment and cataracts. The forelimbs are most noticeably affected, particularly the short radius and ulna, which subsequently develop curvature with varus/valgus deformities (Carrig et al., 1997). In pups, the dome of the cranium is often pronounced and there is moderate excessive exotropic strabismus. Some, but not all, carriers have vitreal stands, focal retinal folds or plaques of retinal dysplasia.
Pathology: There is a range of ocular defects, but the most consistent findings are cortical equatorial cataracts and vitreal liquefaction (Goldstein et al, 2010). Histologic lesions in the growth plates included disorganization of cellular columns with abnormal extent of calcification, great variability in chrondrocyte shape, and premature cellular condensation in the maturation zone (Farnum et al., 1992).
Prevalence: The frequency of the likely causal variant in the overall Labrador retriever population is estimated at 4% (Goldstein et al., 2010).
Stavinohova et al. (2019): the c.700C>T "variant was genotyped in a total of 1,232 dogs. All seven affected NID [Northern Inuit Dogs] were homozygous for the variant allele (T/T), while 31/116 OSD-unaffected NID were heterozygous for the variant (C/T) and 85/116 were homozygous for the wildtype allele (C/C) . . . A subset of 56 NID unrelated at the parent level were analysed to determine an allele frequency of 0.08, estimating carrier and affected rates to be 15% and 0.6% respectively in NID. All 1,109 non-NID were C/C, suggesting the variant is rare or absent in other breeds."
Control: Parents and siblings of affected dogs should be tested. Breeding of affected or carrier dogs is not recommended.
Breeds: Labrador Retriever, Northern Inuit Dog.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|COL9A3||collagen, type IX, alpha 3||Canis lupus familiaris||24||NC_051828.1 (47526060..47541889)||COL9A3||Homologene, Ensembl , NCBI gene|
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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||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|581||Labrador Retriever||Oculoskeletal dysplasia 1||COL9A3||insertion, small (<=20)||Naturally occurring variant||CanFam3.1||24||g.46653422_46653423insG||c.10_11insG||p.(A4Gfs*46)||NM_001197171.1; NP_001184100.1; published as "a 1-base insertion (guanine) in exon 1 that changes a string of four guanines (CFA24: 49,699,847–49,699,850; CanFam2) to a string of five guanines (c.7–10insG). ... (p.A4GX46)" Goldstein et al. (2010). Information in this table has been changed in accordance to HGVS 3'rule and updated to the current reference genome.||2010||20686772|
|1092||Northern Inuit Dog||Oculoskeletal dysplasia 1||COL9A3||nonsense (stop-gain)||Naturally occurring variant||CanFam3.1||24||g.46660067C>T||c.700C>T||p.(R234*)||2019||31415586|
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.
|2020||Iwabe, S., Dufour, V.L., Guzmán, J.M., Holle, D.M., Cohen, J.A., Beltran, W.A., Aguirre, G.D. :|
|Focal/multifocal and geographic retinal dysplasia in the dog-In vivo retinal microanatomy analyses. Vet Ophthalmol 23:292-304, 2020. Pubmed reference: 31746146 . DOI: 10.1111/vop.12725.|
|Sebbag, L., Riggs, A., Carnevale, J. :|
|Oculo-skeletal dysplasia in five Labrador Retrievers. Vet Ophthalmol 23:386-393, 2020. Pubmed reference: 31595625 . DOI: 10.1111/vop.12715.|
|2019||Stavinohova, R., Hartley, C., Burmeister, L.M., Ricketts, S.L., Pettitt, L., Tetas Pont, R., Hitti, R.J., Schofield, E., Oliver, J.A.C., Mellersh, C.S. :|
|Clinical, histopathological and genetic characterisation of oculoskeletal dysplasia in the Northern Inuit Dog. PLoS One 14:e0220761, 2019. Pubmed reference: 31415586 . DOI: 10.1371/journal.pone.0220761.|
|2012||Miyadera, K., Acland, G.M., Aguirre, G.D. :|
|Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm Genome 23:40-61, 2012. Pubmed reference: 22065099 . DOI: 10.1007/s00335-011-9361-3.|
|2010||Goldstein, O., Guyon, R., Kukekova, A., Kuznetsova, TN., Pearce-Kelling, SE., Johnson, J., Aguirre, GD., Acland, GM. :|
|COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia. Mamm Genome 21:398-408, 2010. Pubmed reference: 20686772 . DOI: 10.1007/s00335-010-9276-4.|
|1995||Acland, G.M., Aguirre, G.D. :|
|Oculoskeletal dysplasias in Samoyed and Labrador retriever dogs: nonallelic disorders akin to Stickler-like syndromes affecting humans 2nd international DOGMAP meeting, Cambridge :, 1995.|
|1992||Farnum, C.E., Jones, K., Riis, R., Wilsman, N.J. :|
|Ocular-Chondrodysplasia in Labrador Retriever Dogs - A Morphometric and Electron Microscopical Analysis Calcified Tissue International 50:564-572, 1992. Pubmed reference: 1525714 .|
|1988||Carrig, CB., Sponenberg, DP., Schmidt, GM., Tvedten, HW. :|
|Inheritance of associated ocular and skeletal dysplasia in Labrador retrievers. J Am Vet Med Assoc 193:1269-72, 1988. Pubmed reference: 3204050 .|
|1977||Carrig, C.B., MacMillian, A., Brundage, S., Pool, R.R., Morgan, J.P. :|
|Retinal dysplasia associated with skeletal abnormalities in Labrador Retrievers Journal of the American Veterinary Medical Association 170:49-57, 1977. Pubmed reference: 830631 .|
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