Thr40 and Met122 are new partial loss-of-function natural mutations of the human melanocortin 1 receptor.

Activation by melanocortins of the melanocortin 1 receptor (MC1R), expressed in epidermal melanocytes, stimulates melanogenesis. Human MC1R gene loss-of-function mutations are associated with fair skin, poor tanning and increased skin cancer risk. We identified two natural alleles: Ile40Thr, probably associated with skin types I-II, and Val122Met. Val122Met bound [(125)I][Nle(4), D-Phe(7)]-alpha-melanocyte stimulating hormone with lower affinity than the wild-type. Dose-response curves of cAMP accumulation were right-shifted for both forms. The Val122Met form failed to achieve maximal cAMP responses comparable to the wild-type or Ile40Thr receptors. Thus, the Ile40Thr and Val122Met variants are partial loss-of-function natural mutations of MC1R.