A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken

Author:

Bi Huijuan,Tranell Jonas,Harper Dawn C.,Lin WeifengORCID,Li Jingyi,Hellström Anders R.,Larsson Mårten,Rubin Carl-Johan,Wang ChaoORCID,Sayyab Shumaila,Kerje Susanne,Bed’hom BertrandORCID,Gourichon David,Ito ShosukeORCID,Wakamatsu KazumasaORCID,Tixier-Boichard Michèle,Marks Michael S.,Globisch DanielORCID,Andersson LeifORCID

Abstract

The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin.IG/IGhomozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5thexon of theCatechol-O-methyltransferase containing domain 1gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout ofComtd1in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore,COMTD1overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin.

Funder

Vetenskapsrådet

Knut och Alice Wallenbergs Stiftelse

National Insitute of Health

Publisher

Public Library of Science (PLoS)

Subject

Cancer Research,Genetics (clinical),Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics

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