Abstract
Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the 5′ end of COL9A2 that cosegregates with drd2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed that RNA expression of the respective genes was reduced in affected retinas. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family, regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy.
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References
Acland GM, Aguirre GD (1995) 2nd International DogMap meeting, Cambridge, UK
Ayme S, Preus M (1984) The Marshall and Stickler syndromes: objective rejection of lumping. J Med Genet 21:34–38
Bonnemann CG, Cox GF, Shapiro F, Wu JJ, Feener CA et al (1999) A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dyplasia with mild myopathy. Proc Natl Acad Sci USA 97:1212–1217
Carrig CB, MacMillan A, Brundage S, Pool RR, Morgan JP (1997) Retinal dysplasia associated with skeletal abnormalities in Labrador retrievers. J Am Vet Med Assoc 170:49–57
Czarny-Ratajczak M, Lohiniva J, Rogala P, Kozlowski K, Perälä M et al (2001) A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity. Am J Hum Genet 69:969–980
Du F (2000) Molecular and genetic studies of Oculoskeletal Dysplasia (OSD) in dogs. Ph.D. thesis, Cornell University, Ithaca, NY
Du F, Acland GM, Ray J (2000) Cloning and expression of type II collagen mRNA: evaluation as a candidate for canine oculoskeletal dysplasia. Gene 255:307–316
Fiedler J, Stove J, Heber F, Brenner RE (2002) Clinical phenotype and molecular diagnosis of multiple epiphyseal dysplasia with relative hip sparing during childhood (EDM2). Am J Med Genet 112:144–153
Goldstein O, Zangerl B, Pearce-Kelling S, Sidjanin DJ, Kijas JW et al (2006) Linkage disequilibrium mapping in the domestic dog breeds narrows the progressive rod-cone degeneration interval and identifies ancestral disease-transmitting chromosome. Genomics 88:541–550
Holden P, Canty EG, Mortier GR, Zabel B, Spranger J et al (1999) Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal form of multiple epiphyseal dyplasia. Am J Hum Genet 65:31–38
Kukekova AV, Nelson J, Kuchtey RW, Lowe JK, Johnson JL et al (2006) Linkage mapping of canine rod cone dysplasia type 2 (rcd2) to CFA7, the canine orthologue of human 1q32. Invest Ophthamol Vis Sci 47:1210–1215
Lathrop GM, Lalouel JM, Julier C, Ott J (1984) Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 81:3443–3446
Lohiniva J, Paassilta P, Seppanen U, Vierimaa O, Kivirikko S et al (2000) Splicing mutations in the COL3 domain of collagen IX causes multiple epiphyseal dysplasia. Am J Med Genet 90:216–222
Matise TC, Perlin M, Chakravarti A (1994) Automated construction of genetic linkage maps using an expert system (MultiMap): a human genome linkage map. Nat Genet 6:384–390
Maumenee IH, Traboulsi EI (1985) The ocular findings in Kniest dysplasia. Am J Ophthalmol 100:155–160
Meyers VN, Jezyk PF, Aguirre GD, Patterson DF (1983) Short-limbed dwarfism and ocular defects in the samoyed dog. J Am Vet Med Assoc 183:975–979
Nakashima M, Ikegawa S, Ohashi H, Kimizuka M, Nishimura G (2005a) Double-layered patella in multiple epiphyseal dysplasia is not exclusive to DTDST mutation. Am J Med Genet 133A:106–107
Nakashima M, Kitoh H, Maeda K, Haga N, Kosaki R et al (2005b) Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia. Am J Med Genet 132A:181–184
Paasilta P, Lohiniva J, Annunem S, Bonaventure J, Le-Merrer M et al (1999) COL9A3: a third locus for multiple epiphyseal dysplasia. Am J Hum Genet 64:1036–1044
Pellegrini B, Acland GM, Ray J (2002) Cloning and characterization of opticin cDNA: evaluation as a candidate for canine oculoskeletal dysplasia. Gene 282:121–131
Snead MP, Yates JR (1999) Clinical and molecular genetics of Stickler syndrome. J Med Genet 36:353–359
Spranger JW, Brill PW, Poznanski AK (2002) Multiple epiphyseal dysplasia. In: Spranger JW, Brill PW, Poznanski AK (eds) Bone dysplasia: an atlas of genetic disorders of skeletal development. Oxford University Press, New York, pp 141–146
Stickler GB, Belau PG, Farrell FJ, Jones JD, Pugh DG et al (1965) Hereditary progressive arthro-ophthalmopathy. Mayo Clin Proc 40:433–455
Takahashi M, Matsui Y, Goto T, Nishimura G, Ikegawa S et al (2006) Intrafamilial phenotypic diversity in multiple epiphyseal dysplasia associated with the COL9A2 mutation (EDM2). Clin Rheumatol 25:591–595
Van Camp G, Snoeckx RL, Hilgert N, Ende J, Fukuoka H et al (2006) A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene. Am J Hum Genet 79:449–457
Acknowledgments
The authors thank Julie Jordan and the staff of the RDS facility for excellent technical assistance. Blood samples with pedigrees and clinical reports were provided by Ms. Sue Bailey and Ms. Nancy Scholz for selected Labrador retriever dogs. Leah Seman, Beth A. Tallentire, and Glen Adams, breeders and owners of samoyed dogs, were immensely cooperative and helpful and are gratefully acknowledged. This work was supported by NIH grant EY006855, The Foundation Fighting Blindness, and the Morris Animal Foundation.
Disclosures
G. M. Acland and G. D. Aguirre are co-owners of Optigen, LLC (Ithaca, NY, USA) which has licensed the technology for DNA testing of dogs with OSD from Cornell University.
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Nucleotide sequence data reported here are available in the GenBank database under accession numbers GU075879, GU075880, GU075881, and GU075882.
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Goldstein, O., Guyon, R., Kukekova, A. et al. COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia. Mamm Genome 21, 398–408 (2010). https://doi.org/10.1007/s00335-010-9276-4
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DOI: https://doi.org/10.1007/s00335-010-9276-4