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 ]‐α‐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 .