Bulldog dwarfism in Dexter cattle is caused by mutations in ACAN

• Published in: Mammalian genome Vol. 18; no. 11; pp. 808 - 814
• Main Authors: Cavanagh, Julie A. L, Tammen, Imke, Windsor, Peter A, Bateman, John F, Savarirayan, Ravi, Nicholas, Frank W, Raadsma, Herman W
• Format: Journal Article
• Language: English
• Published: United States New York : Springer-Verlag 01.11.2007; Springer Nature B.V
• Subjects: Aggrecans - genetics; Aggrecans - metabolism; Animals; Base Sequence; cartilage; Cattle; Cattle Diseases - genetics; Cattle Diseases - metabolism; chondrocytes; Chromosome Mapping; Dexter; DNA - genetics; DNA Mutational Analysis; DNA Primers - genetics; Dwarfism - genetics; Dwarfism - metabolism; Dwarfism - veterinary; Exons; Female; fetus; Genes, Lethal; genotyping; heterozygosity; Heterozygote; homozygosity; Homozygote; Humans; legs; loci; Male; messenger RNA; Molecular Sequence Data; mutants; Mutation; Pedigree; Phenotype; Pregnancy; RNA Stability; RNA, Messenger - genetics; screening
• ISSN: 0938-8990; 1432-1777
• DOI: 10.1007/s00335-007-9066-9

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.