|dc.description.abstract||Inherited abnormalities of skeletal development are well documented in humans and domesticated animals, but little is known about the genetic mutations that underpin them. Many inherited skeletal diseases are associated with defective endochondral ossification and are often referred to as chondrodysplasia. Chondrodysplasia is characterised by disproportionate dwarfism and has been described in humans, dogs, cattle, horses, and most recently sheep. The phenotype includes an abnormal skeleton shape and structure, severe skeletal shortening of the limbs and hyperextension of the joints.
In humans, dwarfism is a dominant autosomal mutation and is one of the few genetic disorders known to be caused by a single specific amino acid substitution, located in the Fibroblast Growth Factor Receptor three (FGFR3) gene. FGFR3 is a negative regulator of bone growth functioning to restrict proliferation of pre-bone cartilage at the physes of long bones, limiting skeletal elongation. Disproportionate dwarfism is believed to be a result of an activation mutation in FGFR3, causing severe suppression of chondrocyte growth and bone elongation, resulting in dwarfism.
A new form of dwarfism has recently been observed in two separate populations of Romney and Romney x Coopworth lambs. The lambs have a disproportionate short stature, short legs from knee to fetlock and flat feet; characteristic of chondrodysplasia. Based on the observation that a mutation in FGFR3 is responsible for chondrodysplasia in humans, it was hypothesised that a mutation in FGFR3 was also responsible for the chondrodysplasia observed in the Romney x Coopworth lambs.
Of the 167 sheep studied, the AA genotype was most common, observed in 71% of sheep. No mutation was observed, but all lambs displaying dwarfism had the AA genotype suggesting it may be linked to the phenotype. However it is still impossible to conclude from this that the AA genotype is responsible for dwarfism. The variant frequency of both populations was not in Hardy-Weinberg equilibrium indicating there is a sire effect and more dwarf lambs may be bred in future generations.
The majority of point mutations which cause dwarfism in humans are located within the transmembrane domain of FGFR3; in exon 10. FGFR3 is highly conserved among species which would suggest the mutation for ovine chondrodysplasia would also be in exon 10. However no mutation was observed, suggesting mutations in other genes may be responsible for the skeletal abnormalities observed in the Romney x Coopworth lambs.||en