PAG-VI: IDENTIFICATION OF THE CAUSATIVE MUTATION IN OVINE HEREDITARY CHONDRODYSPLASIA

PAG-VI  Plant & Animal Genome VI Conference

Town & Country Hotel, San Diego, CA, January 18-22, 1998.

W21

IDENTIFICATION OF THE CAUSATIVE MUTATION IN OVINE HEREDITARY CHONDRODYSPLASIA

J E BEEVER1, T L Shay2, J Albretson3, A Maciulis4, T D Bunch2, G R Holyoak2, N E Cockett2

  1. University of Illinois, Department of Animal Sciences, 1201 W. Gregory Drive, Room 210 Edward R. Madigan Laboratory, Urbana, IL 61801
  2. Utah State University, Department of Animal, Dairy & Veterinary Sciences, 315 Biotechnology Center, Logan, UT 84322-4700
  3. National Animal Poison Control Center, Urbana, IL 61802
  4. Utah State University, Center for Persons with Diabilities, Logan, UT 84322-6800

Ovine hereditary chondrodysplasia, commonly called Spider Lamb Syndrome (SLS), is a recessive genetic disorder causing skeletal deformities in young lambs. Common features include abnormally long, bent limbs and curvature of the spine. Since the late 1960's the disorder has spread to several black-faced sheep breeds within the U.S. as well as Suffolks in Canada, Australia and New Zealand. Genetic mapping of the SLS locus was performed by linkage analysis between microsatellite loci in two large pedigrees (n = 303 lambs) produced from matings between carrier individuals. Genetic linkage was detected between four microsatellite markers and SLS, mapping the locus to the distal end of ovine chromosome 6. Comparative analysis of Type I marker maps between sheep, cattle and humans combined with the results of knockout studies in mice identified fibroblast growth factor receptor 3 (FGFR3) as a positional candidate for the disorder. Single-strand conformational polymorphism analysis of ovine FGFR3 identified a polymorphism that co-segregated with the disease in both pedigrees. Genomic and cDNA sequencing of ovine FGFR3 has revealed a single-base mutation causing a non-conservative (non-polar to charged) amino acid substitution in the tyrosine kinase domain of the receptor. Population studies including more than 1000 sheep of differing SLS genotypes demonstrates that this is the causative mutation in SLS. It is most likely that the mutation leads to loss of receptor function in homozygotes that results in poorly controlled chondrocyte differentiation. Further studies of in vitro receptor function are being conducted.

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