The human melanocortin-1 receptor (MC1R) is a G-protein coupled receptor 
involved in the regulation of pigmentation. Several MC1R variant alleles are 
associated with red hair, fair skin and increased skin cancer risk. We have 
performed a systematic functional analysis of nine common MC1R variants and 
correlated these results with the strength of the genetic association of each 
variant allele with pigmentation phenotypes. In vitro expression studies 
revealed that variant receptors with reduced cell surface expression, including 
V60L, D84E, R151C, I155T, R160W and R163Q, showed a corresponding impairment in 
cAMP coupling. The R142H and D294H variants demonstrated normal cell surface 
expression, but had reduced functional responses, indicating that altered 
G-protein coupling may be responsible for this loss of function. The V92M 
variant cAMP activation was equal to or higher than that for wild-type MC1R. In 
co-expression studies, the D84E, R151C, I155T and R160W variants showed a 
dominant negative effect on wild-type receptor cell surface expression, which 
was reflected in a decreased ability to elevate intracellular cAMP levels. The 
D294H variant also demonstrated a dominant negative effect on wild-type MC1R 
cAMP signalling, but had no effect on wild-type surface expression. Importantly, 
comparison of the in vitro receptor characteristics with skin and hair colour 
data of individuals both homozygous and heterozygous for MC1R variant alleles 
revealed parallels between variant MC1R cell surface expression, functional 
ability, dominant negative activity and their effects on human pigmentation. 
These findings show the first direct correlations between variant MC1R 
biochemical properties and pigmentation phenotype.