title: Bulldog dwarfism in Dexter cattle is caused by mutations in ACAN.
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.
authors.affiliation: ReproGen, The University of Sydney, PMB3, Camden, New South Wales 2570, Australia. juliec@camden.usyd.edu.au
authors.forename: Julie A L
authors.initials: JA
authors.lastname: Cavanagh
authors.forename: Imke
authors.initials: I
authors.lastname: Tammen
authors.forename: Peter A
authors.initials: PA
authors.lastname: Windsor
authors.forename: John F
authors.initials: JF
authors.lastname: Bateman
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: Frank W
authors.initials: FW
authors.lastname: Nicholas
authors.forename: Herman W
authors.initials: HW
authors.lastname: Raadsma
mesh_terms: D053674:Aggrecans / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism / Q000662:veterinary*; D005091:Exons; D005260:Female; D005804:Genes, Lethal; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D053674:Aggrecans; D017931:DNA Primers; D012333:RNA, Messenger; D004247:DNA