Mammalian Genome

, Volume 18, Issue 11, pp 808-814

Bulldog dwarfism in Dexter cattle is caused by mutations in ACAN

  • Julie A. L. CavanaghAffiliated withReproGen, The University of Sydney Email author 
  • , Imke TammenAffiliated withReproGen, The University of Sydney
  • , Peter A. WindsorAffiliated withThe University of Sydney
  • , John F. BatemanAffiliated withMusculoskeletal Disorders Theme, Murdoch Childrens Research Institute, Royal Children’s HospitalDepartment of Paediatrics, University of Melbourne
  • , Ravi SavarirayanAffiliated withClinical Genetics Unit, Royal Children’s HospitalSouthern Cross Bone Dysplasia Centre, Genetic Health Services Victoria, Royal Children’s Hospital
  • , Frank W. NicholasAffiliated withReproGen, The University of Sydney
  • , Herman W. RaadsmaAffiliated withReproGen, The University of Sydney

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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.