A Dominant Mutation in G_αs-Protein Increases Hair Pigmentation

We have identified a chemically induced mouse mutation which increases the eumelanic hair pigmentation. We identify a coding mutation, A3533G, resulting in an amino acid substitution Y1133C, in the Gnas gene encoding the G_αs subunit of the tripartite G-protein, consistent with an activation of signalling via MC1R. In addition heterozygous mutant females are significantly lighter than wild type littermates. In cultured melanocytes, derived from mutant mice crossed to C57BL6 mice carrying Cdkn2a^tm1Rdp, basal pigmentation is higher than wild type melanocytes derived from litter mates. However, the addition of exogenous NDP-MSH does not increase pigmentation in mutant melanocytes in contrast to the pigmentation response of non-mutant melanocytes. The mutant and wild type cells respond in the same way to agouti signalling protein (ASP), consistent with ASP signalling mediated through a pathway other than G_αs-protein.