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.
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The authors thank the Australian and overseas Dexter breeders for their generous support in providing samples and information; B. Brenig and J. Williams for European samples; D. Palmer for field support; N. Baker and R. McNeil for help with the mRNA analyses; M. Jones, G. Attard, and C. Kristo for lab support; W. Horton for donation of primers; P. Gilbert for the donation of two carrier female Dexters; and the University of Sydney Veterinary Centre Camden for radiographs. This work was supported by Dexter Cattle Australia Inc. by way of an ARC Linkage grant, and by a theme grant from the Murdoch Children’s Research Institute.
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