Mammalian Genome

, Volume 18, Issue 11, pp 808–814

Bulldog dwarfism in Dexter cattle is caused by mutations in ACAN

  • Julie A. L. Cavanagh
  • Imke Tammen
  • Peter A. Windsor
  • John F. Bateman
  • Ravi Savarirayan
  • Frank W. Nicholas
  • Herman W. Raadsma
Article

Abstract

Bulldog dwarfism in Dexter cattle is one of the earliest single-locus disorders described in animals. Affected fetuses display extreme disproportionate dwarfism, reflecting abnormal cartilage development (chondrodysplasia). Typically, they die around the seventh month of gestation, precipitating a natural abortion. Heterozygotes show a milder form of dwarfism, most noticeably having shorter legs. Homozygosity mapping in candidate regions in a small Dexter pedigree suggested aggrecan (ACAN) as the most likely candidate gene. Mutation screening revealed a 4-bp insertion in exon 11 (2266_2267insGGCA) (called BD1 for diagnostic testing) and a second, rarer transition in exon 1 (−198C>T) (called BD2) that cosegregate with the disorder. In chondrocytes from cattle heterozygous for the insertion, mutant mRNA is subject to nonsense-mediated decay, showing only 8% of normal expression. Genotyping in Dexter families throughout the world shows a one-to-one correspondence between genotype and phenotype at this locus. The heterozygous and homozygous-affected Dexter cattle could prove invaluable as a model for human disorders caused by mutations in ACAN.

Supplementary material

References

  1. Antonsson P, Heingard D, Oldberg A (1989) The keratin sulfate-enriched region of bovine cartilage proteoglycan consists of a consecutively repeated hexapeptide motif. J Biol Chem 264:16170–16173PubMedGoogle Scholar
  2. Barendse W, Vaiman D, Kemp SJ, Sugimoto Y, Armitage SM, et al. (1997) A medium-density genetic linkage map of the bovine genome. Mamm Genome 8:21–8PubMedCrossRefGoogle Scholar
  3. Cavanagh JAL, Tammen I, Hayden MJ, Gill CA, Nicholas FW, et al. (2005) Characterisation of the bovine aggrecan (AGC1) gene: genomic structure and physical and linkage mapping. Anim Genet 36:452–454PubMedCrossRefGoogle Scholar
  4. Chan D, Weng YM, Graham HK, Sillence DO, Bateman JF (1998) A nonsense mutation in the carboxyl-terminal domain of type X collagen causes haploinsufficiency in schmid metaphyseal chondrodysplasia. J Clin Invest 101:1490–1499PubMedCrossRefGoogle Scholar
  5. Curran PL (1990) Kerry and Dexter Cattle and other ancient Irish breeds (Dublin: The Royal Dublin Society)Google Scholar
  6. Frischmeyer PA, Dietz HC (1999) Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet 8:1893–1900PubMedCrossRefGoogle Scholar
  7. Fulop C, Walcz E, Valyon M, Glant TT (1993) Expression of alternatively spliced epidermal growth factor-like domains in aggrecans of different species. Evidence for a novel module. J Biol Chem 268:17377–17383PubMedGoogle Scholar
  8. Fulop C, Cs-Szabo G, Glant TT (1996) Species-specific alternative splicing of the epidermal growth factor- like domain 1 of cartilage aggrecan. Biochem J 319:935–940PubMedGoogle Scholar
  9. Gleghorn L, Ramesar R, Beighton P, Wallis G (2005) A mutation in the variable repeat region of the aggrecan gene (AGC1) causes a form of spondyloepiphyseal dysplasia associated with severe, premature osteoarthritis. Am J Hum Genet 77:484–490PubMedCrossRefGoogle Scholar
  10. Green P, Falls K, Crooks S (YEAR) CRI-MAP documentation, version 2.4, available from P. Green at http://www.caos.kun.nl/tutorials/genomics/CRI-MAP.doc.html
  11. Harper PAW, Latter MR, Nicholas FW, Cook RW, Gill PA (1998) Chondrodysplasia in Australian Dexter cattle. Aust Vet J 76:199–202PubMedGoogle Scholar
  12. Hering TM, Kollar J, Huynh TD (1997) Complete coding sequence of bovine aggrecan: comparative structural analysis. Arch Biochem Biophys 345:259–270PubMedCrossRefGoogle Scholar
  13. Krueger RCJ, Kurima K, Schwartz NB (1999) Completion of the mouse aggrecan gene structure and identification of the defect in the cmd-Bc mouse as a near complete deletion of the murine aggrecan gene. Mamm Genome 10:1119–1125PubMedCrossRefGoogle Scholar
  14. Li Y, Olsen BR (1997) Murine models of human genetic skeletal disorders. Matrix Biol 16:49–52PubMedCrossRefGoogle Scholar
  15. Maquat LE (2002) Nonsense-mediated mRNA decay. Curr Biol 12:R196–R197PubMedCrossRefGoogle Scholar
  16. Oetting WS, Lee HK, Flanders DJ, Wiesner GL, Sellers TA, et al. (1995) Linkage analysis with multiplexed short tandem repeat polymorphisms using infrared fluorescence and M13 tailed primers. Genomics 30:450–458PubMedCrossRefGoogle Scholar
  17. Oldberg A, Antonsson P, Heingard D (1987) The partial amino acid sequence of bovine cartilage proteoglycan, deduced from a cDNA clone, contains numerous Ser-Gly sequences arranged in homologous repeats. Biochem J 243:255–259PubMedGoogle Scholar
  18. Schell T, Kulozik AE, Hentze MW (2002) Integration of splicing, transport and translation to achieve mRNA quality control by the nonsense-mediated decay pathway. Genome Biol 3(3):REVIEWS1006Google Scholar
  19. Seligmann MB (1904) Cretinism in calves. J Pathol Bacteriol 9:311–322CrossRefGoogle Scholar
  20. Singh G, Lykke-Andersen J (2003) New insights into the formation of active nonsense-mediated decay complexes. Trends Biochem Sci 28:464–466PubMedCrossRefGoogle Scholar
  21. Stirpe NS, Argraves WS, Goetinck PF (1987) Chondrocytes from the cartilage proteoglycan-deficient mutant, nanomelia, synthesize greatly reduced levels of the proteoglycan core protein transcript. Dev Biol 124:77–81PubMedCrossRefGoogle Scholar
  22. Velleman SG (2000) The role of the extracellular matrix in skeletal development Poult Sci 79:985–989PubMedGoogle Scholar
  23. Vertel BM (1995) The ins and outs of aggrecan. Trends Cell Biol 5:458–464PubMedCrossRefGoogle Scholar
  24. Vertel BM, Grier BL, Li H, Schwartz NB (1994) The chondrodystrophy, nanomelia: biosynthesis and processing of the defective aggrecan precursor. Biochem J 301:211–216PubMedGoogle Scholar
  25. Wai AW, Ng LJ, Watanabe H, Yamada Y, Tam PP, et al. (1998) Disrupted expression of matrix genes in the growth plate of the mouse cartilage matrix deficiency (cmd) mutant. Dev Genet 22:349–358PubMedCrossRefGoogle Scholar
  26. Watanabe H, Kimata K, Line S, Strong D, Gao LY, et al. (1994) Mouse cartilage matrix deficiency (cmd) caused by a 7 bp deletion in the aggrecan gene. Nat Genet 7:154–157PubMedCrossRefGoogle Scholar
  27. Watanabe H, Nakata K, Kimata K, Nakanishi I, Yamada Y (1997) Dwarfism and age-associated spinal degeneration of heterozygote cmd mice defective in aggrecan. Proc Natl Acad Sci U S A 94:6943–6947PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Julie A. L. Cavanagh
    • 1
  • Imke Tammen
    • 1
  • Peter A. Windsor
    • 2
  • John F. Bateman
    • 3
    • 4
  • Ravi Savarirayan
    • 5
    • 6
  • Frank W. Nicholas
    • 7
  • Herman W. Raadsma
    • 1
  1. 1.ReproGenThe University of SydneyCamdenAustralia
  2. 2.The University of SydneyCamdenAustralia
  3. 3.Musculoskeletal Disorders ThemeMurdoch Childrens Research Institute, Royal Children’s HospitalParkvilleAustralia
  4. 4.Department of PaediatricsUniversity of MelbourneParkvilleAustralia
  5. 5.Clinical Genetics UnitRoyal Children’s HospitalParkvilleAustralia
  6. 6.Southern Cross Bone Dysplasia CentreGenetic Health Services Victoria, Royal Children’s HospitalParkvilleAustralia
  7. 7.ReproGenThe University of SydneyCamdenAustralia

Personalised recommendations