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A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse

2008; Nature Portfolio; Volume: 40; Issue: 8 Linguagem: Inglês

10.1038/ng.185

1546-1718

Gerli Pielberg, Anna Golovko, Elisabeth Sundström, Ino Čurik, Johan Lennartsson, Monika Seltenhammer, Thomas Druml, M. M. Binns, Carolyn Fitzsimmons, Gabriella Lindgren, Kaj Sandberg, R. Baumung, M. Vetterlein, Sara Strömberg, Manfred Grabherr, Claire M. Wade, Kerstin Lindblad‐Toh, Fredrik Pontén, Carl‐Henrik Heldin, Johann Sölkner, Leif Andersson,

Cell Adhesion Molecules Research

Gray horses are born colored but gradually lose hair pigmentation and become white, a trait that is transmitted in an autosomal dominant manner. Leif Andersson and colleagues report that the the mutation causing the Gray phenotype is a 4.6-kb duplication in intron 6 of STX17, which promotes overexpression of both STX17 and the neighboring gene NR4A3 in melanomas from Gray horses. In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP (agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals.