In other species: cattle , dog , horse , red fox , pig , sheep , jaguar , jaguarundi , American black bear , woolly mammoth , domestic cat , rabbit , domestic guinea pig , goat , rock pocket mouse , oldfield mouse , gray squirrel , lesser earless lizard , little striped whiptail , water buffalo , domestic yak , alpaca , , coyote , reindeer , Geoffroy's cat , Colocolo , ass , Arabian camel , Mongolian gerbil , raccoon dog , fallow deer , zebu , lorises , antarctic fur seal

Category: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 266300 (trait) , 155555 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: The extension locus encodes the melanocyte-stimulating hormone receptor (MSHR; now known as MC1R). This receptor controls the level of tyrosinase within melanocytes. Tyrosinase is the limiting enzyme involved in synthesis of melanins: high levels of tyrosinase result in the production of eumelanin (dark colour, e.g. brown or black), while low levels result in the production of phaeomelanin (light colour, e.g. red or yellow). When melanocyte-stimulating hormone (MSH) binds to its receptor, the level of tyrosinase is increased, leading to production of eumelanin. The wild-type allele at the extension locus corresponds to a functional MSHR, and hence to dark pigmentation in the presence of MSH. As explained by Schneider et al. (PLoS Genet 10(2): e1004892; 2015), "The most common causes of melanism (black coat) mutations are gain-of-function alterations in MC1R, or loss-of function alterations in ASIP, which encodes Agouti signaling protein, a paracrine signaling molecule that inhibits MC1R signaling". Mutations in MC1R have been associated with white colouring in several species.

Inheritance: As summarised by Yan et al. (2013), "According to their coat colour phenotype in winter, arctic fox (Alopex lagopus) are divided naturally into two colour morphs: the white and blue, named polar fox and blue fox respectively . . . . The two coat colours are determined by different alleles at the E locus, where the ‘blue’ allele Ed is dominant over the ‘white’ one E (Adalsteinsson et al. 1987)."

Mapping: Tietgen et al. (2021): "Using a whole-genome approach, we identified the MC1R gene as the sole causal gene underlying Arctic fox Vulpes lagopus fur colour."

Molecular basis: The blue (Ed) allele is a haplotype comprising two missense variants (p.Gly5Cys and p.Phe280Cys) (Våge et al., 2005)

Associated gene: