Categories: Pigmentation phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600201 (gene) , 611742 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal incomplete dominant

Disease-related: no

Key variant known: yes

Year key variant first reported: 2014

Cross-species summary: This locus, ASIP, encodes the agouti signalling protein, a peptide antagonist of the melanocyte-stimulating hormone receptor (MC1R), which is the product of the extension locus. 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".

Species-specific symbol: A^Pben

Species-specific description: Gershony et al. (2014): "The Bengal cat breed consists of hybrid animals originally developed from crosses between the domestic cat (Felis silvestris catus) and the Asian leopard cat (Prionailurus bengalensis) ... . An unusual pelage type involving a darker face ‘mask’ and a dark dorsal stripe, commonly referred to as a ‘cape’, is unique to the breed. This ‘charcoal’ pattern does not produce a fully melanistic cat (see OMIA000201-9685 : Coat colour, agouti in Felis catus) but bestows darker and more extended markings ... , suggesting unusual interactions between melanism and patterning genes in the hybrid cats."

Molecular basis: By sequencing a prime comparative candidate locus (ASIP) in Bengal cats, Asian leopard cats and domestic cats, Gershony et al. (2014) showed that the charcoal coat colouration/pattern in Bengal cats is strongly associated with compound heterozygosity for an ASIP haplotype from the euptilura form of Asian leopard cat (called A^Pbe) and the feline non-agouti allele a (ASIP:c.123-124del; Eizirik et al., 2003; see OMIA 000201-9685) from domestic cats. The A^Pbe haplotype, considered by Gershony et al. (2014) to be the wild-type ASIP allele in euptilura Asian leopard cats, differs from the feline agouti (A) "by four synonymous and four non-synonymous exonic SNPs, as well as 19 intronic variants, including a 42-bp deletion in intron 4.” The authors do not know which of these leopard cat variants would independently cause the phenotype. The four missense variants (c.41G>C, p.(Cys14Ser); c.142T>C, p.(Ser48Pro); c.251A>G, p.(Gln84Arg) and c.302A>G, p.Asp101Gly), and possibly the 42-bp deletion in intron 4, have been proposed to be used as associated markers. However, the association between the compound heterozygote A^Pbe/a (ASIP:c.[41G>C;142T>C;251A>G;302A>G];[123-124del]) and charcoal phenotype is not complete. Gershony et al. (2014): "Fifty-six of 64 charcoal Bengals were heterozygous at ASIP, with one domestic cat non-agouti haplotype (a) and one leopard cat haplotype (A^Pbe). Eight Bengals, submitted as charcoal in colouration, had different haplotype combinations. ... Eight of 78 Bengal cats submitted as non-charcoal were homozygous or heterozygous for the leopard cat ASIP haplotype (A^Pbe) and the wild-type domestic haplotype (A)." Additional variants were identified to contribute to a unique haplotype for ASIP exon 2 (c.41G>C, c.110-111GG>AA and c.127A>G) termed A2. "Twenty-four non-charcoal Bengals and one Savannah carried the A2 haplotype with either the domestic cat wild-type agouti (A) or non-agouti (a) haplotypes. ... The A2 haplotype was not detected in the wild felids; therefore, its origin is unknown.” Gershony et al. (2014) conclude that “the allelic relationships of ASIP-A^Pbe with ASIP-A and ASIP-a are not fully understood, and more systematic studies are needed”, and that “other interesting phenotypes may occur when the hybrid cats have agouti haplotypes from different species. … Other wild felid-specific variants will likely affect tabby patterning … as well as other aspects of colouration and morphological variation, each potentially affecting the accuracy of genetic tests.”

Breed: Bengal (Cat) (VBO_0100040).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: