title: Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses.
abstract: During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The "splashed white" pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes.
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Regula
authors.initials: R
authors.lastname: Hauswirth
authors.forename: Bianca
authors.initials: B
authors.lastname: Haase
authors.forename: Marlis
authors.initials: M
authors.lastname: Blatter
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Brooks
authors.forename: Dominik
authors.initials: D
authors.lastname: Burger
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.forename: Vincent
authors.initials: V
authors.lastname: Gerber
authors.forename: Diana
authors.initials: D
authors.lastname: Henke
authors.forename: Jozef
authors.initials: J
authors.lastname: Janda
authors.forename: Rony
authors.initials: R
authors.lastname: Jude
authors.forename: K Gary
authors.initials: KG
authors.lastname: Magdesian
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Matthews
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Poncet
authors.forename: Vilhjálmur
authors.initials: V
authors.lastname: Svansson
authors.forename: Teruaki
authors.initials: T
authors.lastname: Tozaki
authors.forename: Lorna
authors.initials: L
authors.lastname: Wilkinson-White
authors.forename: M Cecilia T
authors.initials: MC
authors.lastname: Penedo
authors.forename: Stefan
authors.initials: S
authors.lastname: Rieder
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D003116:Color; D008040:Genetic Linkage; D016678:Genome; D055106:Genome-Wide Association Study; D006200:Hair Color; D006736:Horses / Q000235:genetics*; D008126:Lod Score; D008544:Melanocytes / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D051761:Paired Box Transcription Factors