In other species: taurine cattle , dog , horse , red fox , pig , sheep , jaguar , jaguarundi , American black bear , woolly mammoth , 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 (donkey) , Arabian camel , Mongolian gerbil , raccoon dog , fallow deer , indicine cattle (zebu) , lorises , antarctic fur seal , Przewalski's horse

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 recessive

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2009

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: Peterschmitt et al. (2009): amber in Norwegian Forest cats: c.250G>A; p.Asp84Asn

Gustafson et al. (2017): russet in Burmese cats: 3-bp deletion (c.439_441del; p.Phe146del)

Abitbol and Gache (2019) reported "a c.640_669del in‐frame deletion that is predicted to cause a p.(Ala214_Ala223del) deletion of 10 amino acids in the protein" as the likely causal variant for an autosomal recessive orange coat colour that develops with age in the Kurilian Bobtail breed. The authors names this the Copal variant. As the authors describe, the phenotype was reported in "brown tabby cats born with a warm reddish tone and exhibiting a modification of their original colour during their first year of life. Kittens brighten and adults show an apricot‐red colour. Eumelanin disappears from hairs and cats become very similar to red cats (X‐linked orange locus . . .)". In a personal communication of 6 August 2019, Dr Abitbol advises that "homozygous cats for the variant become red but heterozygous tabby cats are referenced as "golden" by breeders (due to their warm coat colour). It seems that the variant has slight effect on heterozygous tabby cats. But the variant seems to have no effect on heterozygous solid cats."

Bychkova et al. (2020) confirmed the existence and effect of the c.640_669del variant.

Breeds: Burmese (Cat) (VBO_0100053), Kurilian Bobtail (Cat) (VBO_0100146), Norwegian Forest Cat (Cat) (VBO_0100178).

Associated gene: