Canine hip dysplasia has been the subject of intensive study1,2 because some large dog breeds have <50% incidence.3 The trait has a systemic component because multiple joints can be involved,4 yet its most conspicuous manifestation is in the hip joint. Debilitating osteoarthritis, which occurs in affected dogs, adversely affects hip function and gait.
Several investigators have explored the origins of hip joint laxity and instability in the supporting structures of the hip joint, especially the hip joint capsule and round ligament of the femoral head, because interruption of such support may be a critical initiating feature of dysplastic hip development.5 Lust et al,6 Farese et al,7 and Smith8 reported that hip joint laxity, accompanied by synovial effusion and hypertrophy of the round ligament of the femoral head that signal incipient osteoarthritis, contributed to the pathogenesis of CHD.
On the basis of previous genome-wide linkage analysis and fine mapping,9 we hypothesized that a candidate gene in the QTL interval on CFA11 at 18.5 to 21 cM influenced hip joint laxity, as measured by the DI, in dogs. One gene at 20.3 to 20.5 megabases on CFA11, FBN2, was an attractive positional candidate gene because it encodes for a microfibrillary component of extracellular matrix that is present in fibrous joint capsule and articular cartilage.10 Mutations in FBN2 are associated with congenital contractural arachnodactyly in humans,11 and some affected patients have had joint laxity. The purpose of the study reported here was to determine whether a mutation in FBN2 is associated with CHD and osteoarthritis in dogs.
Canine hip dysplasia
Quantitative trait locus
Ensembl [database online]. Cambridge, England: European Bioinformatics Institute and Wellcome Trust Sanger Institute. Available at: www.ensembl.org/Canis_familiaris/index.html. Accessed May 24, 2009.
Entrez [database online]. Bethesda, Md: National Center for Biotechnology Information. Available at: www.ncbi.nlm.nih.gov/mapview/map_search.cgi?taxid#9615. Accessed May 24, 2009.
UCSC Genome Bioinformatics [database online]. Santa Cruz, Calif: University of California-Santa Cruz. Available at: genome.ucsc.edu. Accessed May 24, 2009.
Integrated DNA Technologies, Coralville, Iowa.
Wizard SV 96, Promega Corp, Madison, Wis.
United States Biochemical Corp, Cleveland, Ohio.
Applied Biosystems, Foster City, Calif.
Gene Codes Corp, Ann Arbor, Mich.
Ambion, Austin, Tex.
Superscript III, Invitrogen, Carlsbad, Calif.
Dako, Carpinteria, Calif.
Zymed Laboratories, Carlsbad, Calif.
Abcam, Cambridge, Mass.
Vector Laboratories Inc, Burlingame, Calif.
Fisher Scientific Research, Waltham, Mass.
Marschall Y, Distl O. Mapping quantitative trait loci for canine hip dysplasia in German Shepherd Dogs. Mamm Genome 2007; 18:861–870.
Kaneene JB, Mostosky UV, Padgett GA. Retrospective cohort study of changes in hip joint phenotype of dogs in the United States. J Am Vet Med Assoc 1997; 211:1542–1544.
Olsewski JM, Lust G, Rendano VT, et al. Degenerative joint disease: multiple joint involvement in young and mature dogs. Am J Vet Res 1983; 44:1300–1308.
Carr AJ, Jefferson RJ, Benson MK. Joint laxity and hip rotation in normal children and in those with congenital dislocation of the hip. J Bone Joint Surg Br 1993; 75:76–78.
Lust G, Beilman WT, Rendano VT. A relationship between degree of laxity and synovial fluid volume in coxofemoral joints of dogs predisposed for hip dysplasia. Am J Vet Res 1980; 41:55–60.
Farese JP, Todhunter RJ, Lust G, et al. Dorsolateral subluxation of hip joints in dogs measured in a weight-bearing position with radiography and computed tomography. Vet Surg 1998; 27:393–405.
Zhu L, Zhang Z, Feng F, et al. Single nucleotide polymorphisms refine QTL intervals for hip joint laxity in dogs. Anim Genet 2008; 39:141–146.
Ramirez F, Dietz HC. Fibrillin-rich microfibrils: structural determinants of morphogenetic and homeostatic events. J Cell Physiol 2007; 213:326–330.
Gupta PA, Putnam EA, Carmical SG, et al. Ten novel FBN2 mutations in congenital contractural arachnodactyly: delineation of the molecular pathogenesis and clinical phenotype. Hum Mutat 2002; 19:39–48.
Todhunter RJ, Acland GM, Olivier M, et al. An outcrossed canine pedigree for linkage analysis of hip dysplasia. J Hered 1999; 90:83–92.
Zhang Z, Zhu L, Sandler J, et al. Estimation of heritabilities, genetic correlations, and breeding values of four traits that collectively define hip dysplasia in dogs. Am J Vet Res 2009; 70:483–492.
Gustafsson PO, Olsson SE, Kasstrom H, et al. Skeletal development of Greyhounds, German Shepherd Dogs and their crossbreed offspring. Acta Radiol Suppl 1975; 344:81–108.
Smith GK, LaFond E, Gregor TP, et al. Within- and between-examiner repeatability of distraction indices of the hip joints in dogs. Am J Vet Res 1997; 58:1076–1077.
Lust G, Williams AJ, Burton-Wurster N, et al. Joint laxity and its association with hip dysplasia in Labrador Retrievers. Am J Vet Res 1993; 54:1990–1999.
Lust G, Todhunter RJ, Erb HN, et al. Repeatability of dorsolateral subluxation scores in dogs and correlation with macroscopic appearance of hip osteoarthritis. Am J Vet Res 2001; 62:1711–1715.
Lust G, Todhunter RJ, Erb HN, et al. Comparison of three radio-graphic methods for diagnosis of hip dysplasia in eight-month-old dogs. J Am Vet Med Assoc 2001; 219:1242–1246.
Todhunter RJ, Mateescu R, Lust G, et al. Quantitative trait loci for hip dysplasia in a cross-breed canine pedigree. Mamm Genome 2005; 16:720–730.
Clark LA, Tsai KL, Steiner JM, et al. Chromosome-specific microsatellite multiplex sets for linkage studies in the domestic dog. Genomics 2004; 84:550–554.
Mateescu RG, Burton-Wurster NI, Tsai K, et al. Identification of quantitative trait loci for osteoarthritis of hip joints in dogs. Am J Vet Res 2008; 69:1294–1300.
Phavaphutanon J, Mateescu RG, Tsai KL, et al. Evaluation of quantitative trait loci for hip dysplasia in Labrador Retrievers. Am J Vet Res 2009; 70:1094–1101.
Zhu L, Zhang Z, Friedenberg S, et al. The long (and winding) road to gene discovery for canine hip dysplasia. Vet J 2009; 181:97–110.
Awano T, Katz ML, O'Brien DP, et al. A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. Mol Genet Metab 2006; 89:254–260.
Chase K, Lawler DF, Adler FR, et al. Bilaterally asymmetric effects of quantitative trait loci (QTLs): QTLs that affect laxity in the right versus left coxofemoral (hip) joints of the dog (Canis familiaris). Am J Med Genet A 2004; 124A:239–247.
Putnam EA, Zhang H, Ramirez F, et al. Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet 1995; 11:456–458.
Kealy RD, Lawler DF, Ballam JM, et al. Evaluation of the effect of limited food consumption on radiographic evidence of osteoarthritis in dogs. J Am Vet Med Assoc 2000; 217:1678–1680.
Vanden Berg-Foels WS, Todhunter RJ, Schwager SJ, et al. Effect of early postnatal body weight on femoral head ossification onset and hip osteoarthritis in a canine model of developmental dysplasia of the hip. Pediatr Res 2006; 60:549–554.
Pascal LE, True LD, Campbell DS, et al. Correlation of mRNA and protein levels: cell type-specific gene expression of cluster designation antigens in the prostate. BMC Genomics 2008; 9:246.
Kielty CM, Baldock C, Lee D, et al. Fibrillin: from microfibril assembly to biomechanical function. Philos Trans R Soc Lond B Biol Sci 2002; 357:207–217.
Chaudhry SS, Gazzard J, Baldock C, et al. Mutation of the gene encoding fibrillin-2 results in syndactyly in mice. Hum Mol Genet 2001; 10:835–843.
Arteaga-Solis E, Gayraud B, Lee SY, et al. Regulation of limb patterning by extracellular microfibrils. J Cell Biol 2001; 154:275–281.
Boregowda R, Paul E, White J, et al. Bone and soft connective tissue alterations result from loss of fibrillin-2 expression. Matrix Biol 2008; 27:661–666.
Hurle JM, Corson G, Daniels K, et al. Elastin exhibits a distinctive temporal and spatial pattern of distribution in the developing chick limb in association with the establishment of the cartilaginous skeleton. J Cell Sci 1994; 107:2623–2634.
Yanagino T, Yuasa K, Nagahama M, et al. Transcriptional regulation of fibrillin-2 gene by E2F family members in chondrocyte differentiation. J Cell Biochem 2009; 106:580–588.
Toma DP, White KP, Hirsch J, et al. Identification of genes involved in Drosophila melanogaster geotaxis, a complex behavioral trait. Nat Genet 2002; 31:349–353.
Todhunter RJ, Lust G. Canine hip dysplasia: pathogenesis. In: Slatter D, ed. Textbook of small animal surgery. 3rd ed. St Louis: WB Saunders Co, 2003;2009–2019.
Greisen HA, Summers BA, Lust G. Ultrastructure of the articular cartilage and synovium in the early stages of degenerative joint disease in canine hip joints. Am J Vet Res 1982; 43:1963–1971.
Hui-Chou CS, Lust G. The type of collagen made by the articular cartilage in joints of dogs with degenerative joint disease. Coll Relat Res 1982; 2:245–256.
Wiltberger H, Lust G. Ultrastructure of canine articular cartilage: comparison of normal and degenerative (osteoarthritic) hip joints. Am J Vet Res 1975; 36:727–740.
Oda H, Igarashi M, Hayashi Y, et al. Soft tissue collagen in congenital dislocation of the hip. Biochemical studies of the ligamentum teres of the femur and the hip joint capsule. Nippon Seikeigeka Gakkai Zasshi 1984; 58:331–338.
Jensen BA, Reimann I, Fredensborg N. Collagen type III predominance in newborns with congenital dislocation of the hip. Acta Orthop Scand 1986; 57:362–365.
Wang EB, Zhao Q, Li LY, et al. Expression of COL1a1 and COL3a1 in the capsule of children with developmental dislocation of the hip [in Chinese]. Zhongguo Dang Dai Er Ke Za Zhi 2008; 10:493–496.
Steinetz BG, Williams AJ, Lust G, et al. Transmission of relaxin and estrogens to suckling canine pups via milk and possible association with hip joint laxity. Am J Vet Res 2008; 69:59–67.
Samuel CS, Sakai LY, Amento EP. Relaxin regulates fibrillin 2, but not fibrillin 1, mRNA and protein expression by human dermal fibroblasts and murine fetal skin. Arch Biochem Biophys 2003; 411:47–55.
Cardinet GH III, Guffy MM, Wallace LJ, et al. Canine hip dysplasia in German Shepherd Dog-Greyhound crossbreeds. J Am Vet Med Assoc 1983; 182:393–395.
Matyas JR, Adams ME, Huang D, et al. Major role of collagen IIB in the elevation of total type II procollagen messenger RNA in the hypertrophic phase of experimental osteoarthritis. Arthritis Rheum 1997; 40:1046–1049.
Hirokawa N, Noda Y. Intracellular transport and kinesin super-family proteins, KIFs: structure, function, and dynamics. Physiol Rev 2008; 88:1089–1118.
Sutter NB, Bustamante CD, Chase K, et al. A single IGF1 allele is a major determinant of small size in dogs. Science 2007; 316:112–115.