In other species: cattle , dog , horse , 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 , 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 dominant

Considered a defect: no

Key variant known: yes

Year key variant first reported: 1997

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: By cloning and sequencing a very likely comparative candidate gene (based on extensive evidence in other mammal species that the Extension (E) locus corresponds to the MC1R gene), Vage et al. (1997) cloned and characterized the fox extension locus, providing strong evidence that the Alaska Silver allele, E(A), which confers dark pigmentation, is due to a C125R amino-acid substitution in the melanocyte-stimulating hormone receptor.

Liu et al. (2016) confirmed the findings by Vage et al. (1997) when they reported that the "c.373T>C in the coding region of the MC1R gene is probably associated with the brown phenotype of chocolate foxes". As Vage et al. (1997) reported protein coordinates for the variant and Liu et al. (2016) reported cDNA coordinates, the variant was initially added twice to OMIA variant tables (OMIA variant IDs 115 and 116). After review of the paper by Vage et al. (1997) and revision of the location on the reference genome the variant information was updated for OMIA variant 115, and OMIA variant 116 was deleted [20/01/2023].

Associated gene: