Categories: Skeleton phene (incl. short stature & teeth) , Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 154780 (trait) , 120270 (gene)

Single-gene trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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; DYSP-COL9A3 (osd1) (Mowat et al., 2024)

Species-specific description: Oculoskeletal dysplasia 1 (osd1, drd1) is a collagen disorder characterized by short-limbed dwarfism, particularly of the forelimbs, and vitreous dysplasia with associated retinal detachment and cataracts. 
See also OMIA:001523-9615 : Oculoskeletal dysplasia 2

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 DNA tested. 

Breeds: Labrador Retriever (Dog) (VBO_0200800), Northern Inuit Dog (Dog) (VBO_0200952).
Breeds in which the phene or likely causal variants have been documented. If a likely causal variant has been documented, see variant-specific breed information in the variant table. (Breed information may be incomplete).

Associated gene: