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

• DOI: 10.1038/ng.185
• Publication Date: 2008-07-20T18:56:03Z
• Authors: Gerli Rosengren P...; Anna Golovko; Elisabeth Sundström; Ino Curik; Johan Lennartsson; Monika H Seltenha...; Thomas Druml; Matthew Binns; Carolyn Fitzsimmons; Gabriella Lindgren; Kaj Sandberg; Roswitha Baumung; Monika Vetterlein; Sara Strömberg; Manfred Grabherr; Claire Wade; Kerstin Lindblad-Toh; Fredrik Pontén; Carl-Henrik Heldin; Johann Sölkner; Leif Andersson
• Keywords: Melanocortin 1 receptor; Vitiligo; Depigmentation; Pigmentation disorder

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.