Molecular and pharmacological characterization of dominant black coat color in sheep

Dominant black coat color in sheep is predicted to be caused by an allele E -D at the extension locus. Recent studies have shown that this gene encodes the melanocyte stimulating hormone receptor (MC1-R). In mouse and fox, nat urally occurring mutations in the coding region of MC1-R produce a constitu tively activated receptor that switches the synthesis from phaeomelanin to eumelanin within the melanocyte, explaining the black coat color observed p henotypically. In the sheep, we have identified a Met-->Lys mutation in pos ition 73 (M73K) together with a Asp --> Asn change at position 121 (D121N) showing complete cosegregation with dominant black coat color in a family l ineage. Only the M73K mutation showed constitutive activation when introduc ed into the corresponding mouse receptor (mMC1-R) for pharmacological analy sis, however, the position corresponding to D121 in the mouse receptor is r equired for high affinity ligand binding. The pharmacological profile of th e M73K change is unique compared to the constitutively active E92K mutation in the sombre mouse and C123R mutation in the Alaska silver fox, indicatin g that the M73K change activates the receptor via a mechanism distinct from these previously characterized mutations.