Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses

Regula Hauswirth, Bianca Haase, Marlis Blatter, Samantha A. Brooks, Dominik Burger, Cord Drögemüller, Vincent Gerber, Diana Henke, Jozef Janda, Rony Jude, K G Magdesian, Jacqueline M. Matthews, Pierre André Poncet, Vilhjálmur Svansson, Teruaki Tozaki, Lorna Wilkinson-White, Cecilia Penedo, Stefan Rieder, Tosso Leeb

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere1002653
JournalPLoS Genetics
Volume8
Issue number4
DOIs
StatePublished - Apr 2012

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Metrorrhagia
horse
Horses
phenotype
mutation
Phenotype
horses
Mutation
Quarter Horse
melanocytes
genes
gene
linkage (genetics)
promoter regions
monogenic inheritance
Genes
Melanocytes
horse breeds
missense mutation
neural crest

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Hauswirth, R., Haase, B., Blatter, M., Brooks, S. A., Burger, D., Drögemüller, C., ... Leeb, T. (2012). Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses. PLoS Genetics, 8(4), [e1002653]. https://doi.org/10.1371/journal.pgen.1002653

Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses. / Hauswirth, Regula; Haase, Bianca; Blatter, Marlis; Brooks, Samantha A.; Burger, Dominik; Drögemüller, Cord; Gerber, Vincent; Henke, Diana; Janda, Jozef; Jude, Rony; Magdesian, K G; Matthews, Jacqueline M.; Poncet, Pierre André; Svansson, Vilhjálmur; Tozaki, Teruaki; Wilkinson-White, Lorna; Penedo, Cecilia; Rieder, Stefan; Leeb, Tosso.

In: PLoS Genetics, Vol. 8, No. 4, e1002653, 04.2012.

Research output: Contribution to journalArticle

Hauswirth, R, Haase, B, Blatter, M, Brooks, SA, Burger, D, Drögemüller, C, Gerber, V, Henke, D, Janda, J, Jude, R, Magdesian, KG, Matthews, JM, Poncet, PA, Svansson, V, Tozaki, T, Wilkinson-White, L, Penedo, C, Rieder, S & Leeb, T 2012, 'Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses', PLoS Genetics, vol. 8, no. 4, e1002653. https://doi.org/10.1371/journal.pgen.1002653
Hauswirth R, Haase B, Blatter M, Brooks SA, Burger D, Drögemüller C et al. Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses. PLoS Genetics. 2012 Apr;8(4). e1002653. https://doi.org/10.1371/journal.pgen.1002653
Hauswirth, Regula ; Haase, Bianca ; Blatter, Marlis ; Brooks, Samantha A. ; Burger, Dominik ; Drögemüller, Cord ; Gerber, Vincent ; Henke, Diana ; Janda, Jozef ; Jude, Rony ; Magdesian, K G ; Matthews, Jacqueline M. ; Poncet, Pierre André ; Svansson, Vilhjálmur ; Tozaki, Teruaki ; Wilkinson-White, Lorna ; Penedo, Cecilia ; Rieder, Stefan ; Leeb, Tosso. / Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses. In: PLoS Genetics. 2012 ; Vol. 8, No. 4.
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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.",
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AU - Haase, Bianca

AU - Blatter, Marlis

AU - Brooks, Samantha A.

AU - Burger, Dominik

AU - Drögemüller, Cord

AU - Gerber, Vincent

AU - Henke, Diana

AU - Janda, Jozef

AU - Jude, Rony

AU - Magdesian, K G

AU - Matthews, Jacqueline M.

AU - Poncet, Pierre André

AU - Svansson, Vilhjálmur

AU - Tozaki, Teruaki

AU - Wilkinson-White, Lorna

AU - Penedo, Cecilia

AU - Rieder, Stefan

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