Thr40 and Met122 are new partial loss-of-function natural mutations of thehuman melanocortin 1 receptor

Activation by melanocortins of the melanocortin 1 receptor (MC1R), expresse d in epidermal melanocytes, stimulates melanogenesis. Human MC1R gene loss- of-function mutations are associated with fair skin, poor tanning and incre ased skin cancer risk. We identified two natural alleles: Ile40Thr, probabl y associated with skin types I-II, and Val122Met. Val122Met bound [I-125][N le(4), D-Phe(7)]-alpha -melanocyte stimulating hormone with lower affinity than the wild-type. Dose-response curves of cAMP accumulation were right-sh ifted for both forms. The Val122Met form failed to achieve maximal cAMP res ponses comparable to the wild-type or Ile40Thr receptors. Thus, the Ile40Th r and Val122Met variants are partial loss-of-function natural mutations of MC1R. (C) 2001 Federation of European Biochemical Societies. Published by E lsevier Science B.V. All rights reserved.