title: A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, SE-751 24 Uppsala, Sweden.
authors.forename: Gerli
authors.initials: G
authors.lastname: Rosengren Pielberg
authors.forename: Anna
authors.initials: A
authors.lastname: Golovko
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sundström
authors.forename: Ino
authors.initials: I
authors.lastname: Curik
authors.forename: Johan
authors.initials: J
authors.lastname: Lennartsson
authors.forename: Monika H
authors.initials: MH
authors.lastname: Seltenhammer
authors.forename: Thomas
authors.initials: T
authors.lastname: Druml
authors.forename: Matthew
authors.initials: M
authors.lastname: Binns
authors.forename: Carolyn
authors.initials: C
authors.lastname: Fitzsimmons
authors.forename: Gabriella
authors.initials: G
authors.lastname: Lindgren
authors.forename: Kaj
authors.initials: K
authors.lastname: Sandberg
authors.forename: Roswitha
authors.initials: R
authors.lastname: Baumung
authors.forename: Monika
authors.initials: M
authors.lastname: Vetterlein
authors.forename: Sara
authors.initials: S
authors.lastname: Strömberg
authors.forename: Manfred
authors.initials: M
authors.lastname: Grabherr
authors.forename: Claire
authors.initials: C
authors.lastname: Wade
authors.forename: Kerstin
authors.initials: K
authors.lastname: Lindblad-Toh
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Johann
authors.initials: J
authors.lastname: Sölkner
authors.forename: Leif
authors.initials: L
authors.lastname: Andersson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D020440:Gene Duplication; D020022:Genetic Predisposition to Disease; D006200:Hair Color / Q000235:genetics*; D006736:Horses; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D050765:Qa-SNARE Proteins / Q000235:genetics* / Q000378:metabolism; D044102:Receptor, Melanocortin, Type 1 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D012641:Selection, Genetic
chemical_list: D050765:Qa-SNARE Proteins; D044102:Receptor, Melanocortin, Type 1; D018160:Receptors, Cytoplasmic and Nuclear