In other species: cattle , dog , horse , red fox , pig , sheep , jaguar , jaguarundi , American black bear , woolly mammoth , domestic cat , rabbit , domestic guinea pig , goat , Arctic fox , 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 , 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

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2018

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.

Molecular basis: Adopting the comparative candidate gene approach, Almathen et al. (2018) sequenced the MC1R gene in "91 animals from ten Arabian camel populations, that included the four predominant coat color phenotypes observed in the dromedary (light brown, dark brown, black and white)". They identified a missense variant (c.901C>T; p.R301C) associated with white versus non-white: "All nonwhite individuals (black, dark, and light brown, n = 70) were homozygous for the 901C allele, whereas all white dromedaries (Wodh population, n = 21) were either homozygous for the 901T (n = 8) or heterozygous (n = 13) for the 901C/T alleles . . . (P < 0.0001, df = 1)."

Alshanbari et al. (2019) reported that "heterozygosity for . . . [the] missense mutation c.901C > T in MC1R is sufficient for the white coat color suggesting a possible dominant negative effect."

Associated gene: