• 1.

    Lust G. An overview of the pathogenesis of canine hip dysplasia. J Am Vet Med Assoc 1997; 210:14431445.

  • 2.

    Marschall Y, Distl O. Mapping quantitative trait loci for canine hip dysplasia in German Shepherd Dogs. Mamm Genome 2007; 18:861870.

  • 3.

    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; 211:15421544.

    • Search Google Scholar
    • Export Citation
  • 4.

    Olsewski JM, Lust G, Rendano VT, et al. Degenerative joint disease: multiple joint involvement in young and mature dogs. Am J Vet Res 1983; 44:13001308.

    • Search Google Scholar
    • Export Citation
  • 5.

    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; 75:7678.

    • Search Google Scholar
    • Export Citation
  • 6.

    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; 41:5560.

    • Search Google Scholar
    • Export Citation
  • 7.

    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; 27:393405.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Smith GK. Advances in diagnosing canine hip dysplasia. J Am Vet Med Assoc 1997; 210:14511457.

  • 9.

    Zhu L, Zhang Z, Feng F, et al. Single nucleotide polymorphisms refine QTL intervals for hip joint laxity in dogs. Anim Genet 2008; 39:141146.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Ramirez F, Dietz HC. Fibrillin-rich microfibrils: structural determinants of morphogenetic and homeostatic events. J Cell Physiol 2007; 213:326330.

  • 11.

    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; 19:3948.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Todhunter RJ, Acland GM, Olivier M, et al. An outcrossed canine pedigree for linkage analysis of hip dysplasia. J Hered 1999; 90:8392.

  • 13.

    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; 70:483492.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Gustafsson PO, Olsson SE, Kasstrom H, et al. Skeletal development of Greyhounds, German Shepherd Dogs and their crossbreed offspring. Acta Radiol Suppl 1975; 344:81108.

    • Search Google Scholar
    • Export Citation
  • 15.

    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; 58:10761077.

    • Search Google Scholar
    • Export Citation
  • 16.

    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; 54:19901999.

    • Search Google Scholar
    • Export Citation
  • 17.

    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; 62:17111715.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    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; 219:12421246.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Todhunter RJ, Mateescu R, Lust G, et al. Quantitative trait loci for hip dysplasia in a cross-breed canine pedigree. Mamm Genome 2005; 16:720730.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Clark LA, Tsai KL, Steiner JM, et al. Chromosome-specific microsatellite multiplex sets for linkage studies in the domestic dog. Genomics 2004; 84:550554.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    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; 69:12941300.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Phavaphutanon J, Mateescu RG, Tsai KL, et al. Evaluation of quantitative trait loci for hip dysplasia in Labrador Retrievers. Am J Vet Res 2009; 70:10941101.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Heath SC. Markov chain Monte Carlo segregation and linkage analysis for oligogenic models. Am J Hum Genet 1997; 61:748760.

  • 24.

    Rozen S, Skaletsky H. Primer 3 on the WWW for general users and for biologist programmers. Methods Mol Biol 2000; 132:365386.

  • 25.

    Zhu L, Zhang Z, Friedenberg S, et al. The long (and winding) road to gene discovery for canine hip dysplasia. Vet J 2009; 181:97110.

  • 26.

    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; 89:254260.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    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:239247.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Putnam EA, Zhang H, Ramirez F, et al. Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet 1995; 11:456458.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    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; 217:16781680.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    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; 60:549554.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Jansen RC, Nap JP, Mlynárová L. Errors in genomics and proteomics. Nat Biotechnol 2002; 20:19.

  • 32.

    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.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Kielty CM, Baldock C, Lee D, et al. Fibrillin: from microfibril assembly to biomechanical function. Philos Trans R Soc Lond B Biol Sci 2002; 357:207217.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Chaudhry SS, Gazzard J, Baldock C, et al. Mutation of the gene encoding fibrillin-2 results in syndactyly in mice. Hum Mol Genet 2001; 10:835843.

  • 35.

    Arteaga-Solis E, Gayraud B, Lee SY, et al. Regulation of limb patterning by extracellular microfibrils. J Cell Biol 2001; 154:275281.

  • 36.

    Boregowda R, Paul E, White J, et al. Bone and soft connective tissue alterations result from loss of fibrillin-2 expression. Matrix Biol 2008; 27:661666.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    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; 107:26232634.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38.

    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; 106:580588.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39.

    Toma DP, White KP, Hirsch J, et al. Identification of genes involved in Drosophila melanogaster geotaxis, a complex behavioral trait. Nat Genet 2002; 31:349353.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Walji AH. Some histological aspects of the hip joint capsule in the vervet monkey. J Morphol 1988; 197:327335.

  • 41.

    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;20092019.

    • Search Google Scholar
    • Export Citation
  • 42.

    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; 43:19631971.

    • Search Google Scholar
    • Export Citation
  • 43.

    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; 2:245256.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44.

    Wiltberger H, Lust G. Ultrastructure of canine articular cartilage: comparison of normal and degenerative (osteoarthritic) hip joints. Am J Vet Res 1975; 36:727740.

    • Search Google Scholar
    • Export Citation
  • 45.

    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; 58:331338.

    • Search Google Scholar
    • Export Citation
  • 46.

    Jensen BA, Reimann I, Fredensborg N. Collagen type III predominance in newborns with congenital dislocation of the hip. Acta Orthop Scand 1986; 57:362365.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47.

    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; 10:493496.

    • Search Google Scholar
    • Export Citation
  • 48.

    Madsen JS. The joint capsule and joint laxity in dogs with hip dysplasia. J Am Vet Med Assoc 1997; 210:14631465.

  • 49.

    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; 69:5967.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50.

    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; 411:4755.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51.

    Cardinet GH III, Guffy MM, Wallace LJ, et al. Canine hip dysplasia in German Shepherd Dog-Greyhound crossbreeds. J Am Vet Med Assoc 1983; 182:393395.

    • Search Google Scholar
    • Export Citation
  • 52.

    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; 40:10461049.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53.

    Hirokawa N, Noda Y. Intracellular transport and kinesin super-family proteins, KIFs: structure, function, and dynamics. Physiol Rev 2008; 88:10891118.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54.

    Sutter NB, Bustamante CD, Chase K, et al. A single IGF1 allele is a major determinant of small size in dogs. Science 2007; 316:112115.

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Evaluation of a fibrillin 2 gene haplotype associated with hip dysplasia and incipient osteoarthritis in dogs

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  • 1 Department of Clinical Sciences
  • | 2 Department of Statistics, College of Arts and Sciences, Oklahoma State University, Stillwater, OK 74078
  • | 3 Institute for Genomic Diversity, College of Agriculture and Life Sciences
  • | 4 Department of Clinical Sciences
  • | 5 Biotechnology Resource Center Cornell University, Ithaca, NY 14853
  • | 6 Microarray Core Facility
  • | 7 Department of Biomedical Sciences
  • | 8 Department of Clinical Sciences
  • | 9 James A. Baker Institute for Animal Health College of Veterinary Medicine
  • | 10 Department of Clinical Sciences
  • | 11 Department of Clinical Sciences
  • | 12 Department of Biomedical Sciences
  • | 13 Department of Clinical Sciences
  • | 14 Department of Clinical Sciences
  • | 15 Department of Biomedical Sciences
  • | 16 James A. Baker Institute for Animal Health College of Veterinary Medicine
  • | 17 Department of Clinical Sciences
  • | 18 Department of Clinical Sciences
  • | 19 Department of Biomedical Sciences
  • | 20 Department of Clinical Sciences

Abstract

Objective—To determine whether a mutation in the fibrillin 2 gene (FBN2) is associated with canine hip dysplasia (CHD) and osteoarthritis in dogs.

Animals—-1,551 dogs.

Procedures—Hip conformation was measured radiographically. The FBN2 was sequenced from genomic DNA of 21 Labrador Retrievers and 2 Greyhounds, and a haplotype in intron 30 of FBN2 was sequenced in 90 additional Labrador Retrievers and 143 dogs of 6 other breeds. Steady-state values of FBN2 mRNA and control genes were measured in hip joint tissues of fourteen 8-month-old Labrador Retriever–Greyhound crossbreeds.

Results—The Labrador Retrievers homozygous for a 10-bp deletion haplotype in intron 30 of FBN2 had significantly worse CHD as measured via higher distraction index and extended-hip joint radiograph score and a lower Norberg angle and dorsolateral subluxation score. Among 143 dogs of 6 other breeds, those homozygous for the same deletion haplotype also had significantly worse radiographic CHD. Among the 14 crossbred dogs, as the dorsolateral subluxation score decreased, the capsular FBN2 mRNA increased significantly. Those dogs with incipient hip joint osteoarthritis had significantly increased capsular FBN2 mRNA, compared with those dogs without osteoarthritis. Dogs homozygous for the FBN2 deletion haplotype had significantly less FBN2 mRNA in their femoral head articular cartilage.

Conclusions and Clinical Relevance—The FBN2 deletion haplotype was associated with CHD. Capsular gene expression of FBN2 was confounded by incipient secondary osteoarthritis in dysplastic hip joints. Genes influencing complex traits in dogs can be identified by genome-wide screening, fine mapping, and candidate gene screening.

Abstract

Objective—To determine whether a mutation in the fibrillin 2 gene (FBN2) is associated with canine hip dysplasia (CHD) and osteoarthritis in dogs.

Animals—-1,551 dogs.

Procedures—Hip conformation was measured radiographically. The FBN2 was sequenced from genomic DNA of 21 Labrador Retrievers and 2 Greyhounds, and a haplotype in intron 30 of FBN2 was sequenced in 90 additional Labrador Retrievers and 143 dogs of 6 other breeds. Steady-state values of FBN2 mRNA and control genes were measured in hip joint tissues of fourteen 8-month-old Labrador Retriever–Greyhound crossbreeds.

Results—The Labrador Retrievers homozygous for a 10-bp deletion haplotype in intron 30 of FBN2 had significantly worse CHD as measured via higher distraction index and extended-hip joint radiograph score and a lower Norberg angle and dorsolateral subluxation score. Among 143 dogs of 6 other breeds, those homozygous for the same deletion haplotype also had significantly worse radiographic CHD. Among the 14 crossbred dogs, as the dorsolateral subluxation score decreased, the capsular FBN2 mRNA increased significantly. Those dogs with incipient hip joint osteoarthritis had significantly increased capsular FBN2 mRNA, compared with those dogs without osteoarthritis. Dogs homozygous for the FBN2 deletion haplotype had significantly less FBN2 mRNA in their femoral head articular cartilage.

Conclusions and Clinical Relevance—The FBN2 deletion haplotype was associated with CHD. Capsular gene expression of FBN2 was confounded by incipient secondary osteoarthritis in dysplastic hip joints. Genes influencing complex traits in dogs can be identified by genome-wide screening, fine mapping, and candidate gene screening.

Contributor Notes

Address correspondence to Dr. Todhunter (rjt2@cornell.edu).

Supported by Collaborative Research Grant program in the College of Veterinary Medicine, Cornell Biotechnology, the Morris Animal Foundation, the NHLBI Mammalian Genotyping Service, and NIH grant No. 1 R21 AR055228–01A1.

Presented as a poster at the Annual Meeting of the Morris Animal Foundation, Boulder, Colo, June 2007.

The authors thank Alma Jo Williams for technical assistance and Dr. Jody Sandler for contribution of hip joint radiographs and blood samples.