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

Categories: 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

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2006

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.

Species-specific description: See Robinson (1958, pp. 248-251)

Molecular basis: Fontanesi et al. (2006) reported that the recessive (red) e allele is "a 30-nucleotide in-frame deletion (c.304_333del30)"; and "a 6-nucleotide in-frame deletion (c.280_285del6) . . . may be allele E(D) or allele E(S) [dominant black]". Fontanesi et al. (2010) showed that allele eJ (Extension Japanese allele) is determined by a 6 bp in-frame deletion flanked by a G>A transition in 5' (c.124G>A;125_130del6) in the MC1R gene. In homozygous eJ/eJ rabbits, this allele is expressed in skin areas with black hair, whereas it is not expressed in skin with red hair areas (Fontanesi et al., 2010). [Based on wording provided by Luca Fontanesi to FN] By using the CRISPR/Cas9 system, Xiao et al. (2019) bred rabbits with a light yellow coat colour by creating deletions in the MC1R gene. These rabbits are genetically-modified organiams (GMO).

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Breeds: Angora (Rabbit) (VBO_0001228), California (Rabbit) (VBO_0001239), Champagne-Silberkaninchen, Germany (Rabbit) (VBO_0013836), Checkered Giant, Checkered Small, Coloured dwarf, Dutch (Rabbit) (VBO_0001245), English Lop, English Spot (Rabbit) (VBO_0001246), Fauve de Borgogne (Rabbit) (VBO_0001248), Giant Grey, Japanese (Rabbit) (VBO_0001259), Lop, Lop dwarf, New Zealand Red (Rabbit) (VBO_0001268), New Zealand White (Rabbit) (VBO_0001269), Rheinische Schecken (Rabbit) (VBO_0001275), Saxon Gold, Thüringer (Rabbit) (VBO_0001283), White Giant (Rabbit) (VBO_0001287).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: