Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600042 (gene)

Mendelian trait/disorder: yes

Disease-related: no

Key variant known: yes

Year key variant first reported: 2016

Inheritance: The exact mode of inheritance for hair shedding has not been published. Hayward et al. (2016) documented epistatic interactions of MC5R with FGF5 and RSPO2, which also affect hair morphology in dogs.

Mapping: Hayward et al. (2016) used 1873 dogs from 158 breeds in GWAS for various morphological traits. Phenotypes for fur length and extent of hair shedding were based on breed averages. Two independent GWAS identified the same locus on chromosome 1 harboring the MC5R gene associated with fur length and extent of hair shedding.

Molecular basis: Hayward et al. (2016) included a missense variant in the MC5R gene (p.A237T) in their GWAS for hair length and extent of hair shedding that had previously been identified in village dogs. In both GWAS, this variant was the strongest associated marker. Based on in silico structure modeling Hayward et al. (2016) found "evidence that the A237T mutation causes a conformational change in the tertiary structure of the protein, with a change in binding sites ... that is ‘probably damaging’ (Polyphen-2 HumDiv = 0.992)." MC5R is expressed in sebaceous glands and involved in the production of sebum. Hayward et al. (2016) cautioned "While functional studies are needed to determine whether this variant is indeed the causal mutation at this QTL" and concluded "the identification of a third coat length locus improves our understanding of fur-type genetics in the dog and hypothesizes a relationship between sebum production and fur type in some breeds."

Clinical features: The derived allele at MC5R (237-Thr) is associated with reduced hair shedding and shorter hair length. However, epistatic interactions with the genotypes at MC5R, RSPO2 and FGF5 exist (Hayward et al. 2016).

Associated gene: