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Human Molecular Genetics, 2001, Vol. 10, No. 21 2397-2402
© 2001 Oxford University Press

Functional variation of MC1R alleles from red-haired individuals

Eugene Healy, Siobhán A. Jordan, Peter S. Budd, Ruth Suffolk, Jonathan L. Rees1 and Ian J. Jackson+

MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK and 1Department of Dermatology, University of Edinburgh, Lauriston Building, The Royal Infirmary, Edinburgh EH3 9YW, UK

Red hair in humans is associated with variant alleles of the {alpha}MSH receptor gene, MC1R. Loss of MC1R function in other mammals results in red or yellow hair pigmentation. We show that a mouse bacterial artificial chromosome (BAC) which contains Mc1r will efficiently rescue loss of Mc1r in transgenic mice, and that overexpression of the receptor suppresses the effect of the endogenous antagonist, agouti protein. We engineered the BAC to replace the mouse coding region with the human MC1R sequence and used this in the transgenic assay. The human receptor also efficiently rescued Mc1r deficiency, and in addition, appeared to be completely resistant to the effects of agouti, suggesting agouti protein may not play a role in human pigmentary variation. Three human variant alleles account for 60% of all cases of red hair. We engineered each of these in turn into the BAC and find that they have reduced, but not completely absent, function in transgenic mice. Comparison of the phenotypes of {alpha}MSH-deficient mice and humans in conjunction with this data suggests that red hair may not be the null phenotype of MC1R.

+ To whom correspondence should be addressed. Tel: +44 131 467 8409; Fax: +44 131 343 2620; Email: ian.jackson@hgu.mrc.ac.ukThe authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First AuthorsPresent address:Eugene Healy, Dermatopharmacology, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK


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