Table 2

 Human subject genotypes and phenotypes

GenotypeNo. of variantsGenotype*n (%)†Phenotype‡
*Experiments in transfected cell lines have determined that the following MC1R variants are unable to induce cyclic AMP production when stimulated by α-melanocyte stimulating hormone (α-MSH) or a long lasting analogue, NDP(Nle,4 D-Phe7)-MSH (see Schaffer and Bolognia8): R142H (Arg142His), R151C (Arg151Cys), R160W (Arg160Trp), D294H (Asp294His), and the insertion mutations ins29 and ins179. The R142H and insertion mutations are very rare (<1% allele frequency), and were not seen in this study except for one subject homozygous for ins29. Subjects with two (or in one case, three) total variants at ins29, R151C, R160W, and/or D294H (all redheads) were thus classified in the non-functional MC1R genotype group (“2+”). The V60L (Val60Leu) and V92M (Val92Met) are somewhat common mutations, but do not lead to MC1R loss of function, and thus subjects with these MC1R variants were classed with the functional MC1R genotype group (“0/1”). R163Q (Arg163Gln) has not yet been tested for cAMP stimulation; we conservatively classified this variant as not affecting MC1R function. It should be noted that the genotypic effect on both baseline sensitivity and M6G analgesia is significant at the p<0.05 level regardless of the classification of R163Q containing subjects. We also assayed for the K65N (Lys65Asn) and D84E (Asp84Glu) variants, but found none.
†Percentages do not add up to 100% due to rounding. Allele frequencies in these subjects were: +/+ (wildtype): 31%; ins29: 2%; V60L: 6%; V92M: 3%; R151C: 27%; R160W: 26%; R163Q: 2%; D294H: 3%. These values agree well with those previously reported in the literature.
‡Subjects classified as “redheads” had red hair ranging from orange to auburn, fair (type I/II) skin, and blue or green eyes. Twenty two of the 29 redheads (76%) possessed two or more MC1R inactivating variants, also in excellent agreement with the existing literature.
+/+ (consensus sequence)00/110 (21%)All non-redhead
V60L/+10/12 (4%)Both non-redhead
V92M/+10/11 (2%)Non-redhead
R151C/+10/13 (6%)1 Non-redhead; 2 redheads
R160W/+10/13 (6%)2 Non-redheads; 1 redhead
V60L/V60L20/11 (2%)Non-redhead
V60L/V92M20/11 (2%)Non-redhead
V60L/D294H20/11 (2%)Redhead
V92M/D294H20/11 (2%)Redhead
R151C/R163Q20/11 (2%)Redhead
R160W/R163Q20/11 (2%)Redhead
ins29/ins2922+1 (2%)Redhead
R151C/R151C22+3 (6%)All redheads
R151C/R160W22+12 (26%)All redheads
R151C/D294H22+1 (2%)Redhead
R160W/R160W22+4 (9%)All redheads
R151C/R151C and R160W/+32+1 (2%)Redhead
Totals0/1: 2547Non-redheads: 18
2+: 22Redheads: 29