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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.
Publication Date: 2012-04-12 PubMed ID: 22511888PubMed Central: PMC3325211DOI: 10.1371/journal.pgen.1002653Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
- Research Support
- U.S. Gov't
- Non-P.H.S.
Summary
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The study investigates how mutations in the MITF and PAX3 genes contribute to “splashed white” and other white spotting patterns, characteristic of diverse horse phenotypes.
Background
- The processes of fetal development include the migration of melanoblasts, derived from neural crest, across the entire body surface, where they differentiate into melanocytes, or pigment-producing cells.
- Alterations to this precisely regulated process can result in variations known as white spotting patterns. These patterns in horses exhibit a significantly wide phenotypic variety, ranging from minimal white markings to completely white horses.
- The “splashed white” pattern is primarily identified by a large blaze, usually accompanied by extended white markings on distal limbs and blue eyes. A subset of splashed white horses is deaf.
Research Methodology
- This research analyzed a Quarter Horse family with the splashed white coat color. A genome-wide linkage study in 31 horses resulted in a positive LOD score of 1.6 in a region on chromosome 6, which contains the PAX3 gene. Nevertheless, the linkage data did not concur with a single monogenic inheritance of a fully penetrant mutation.
- When the PAX3 gene was sequenced, a missense mutation was identified in some, but not all, splashed white Quarter Horses in the study.
- A genome-wide association analysis suggested another potential signal close to the MITF gene. The sequencing of this gene revealed a 10 bp insertion in the melanocyte-specific promoter.
Findings
- The variant in the MITF promoter was found both in the studied splashed white Quarter Horse family and in splashed white horses from other breeds.
- Two additional non-synonymous mutations in the MITF gene were identified in unrelated horses with white spotting phenotypes.
- Consequently, it was concluded that multiple independent mutations in the MITF and PAX3 genes, along with known variants in the EDNRB and KIT genes, explain a significant percentage of horses with more extreme white spotting phenotypes.
Cite This Article
APA
Hauswirth R, Haase B, Blatter M, Brooks SA, Burger D, Dru00f6gemu00fcller C, Gerber V, Henke D, Janda J, Jude R, Magdesian KG, Matthews JM, Poncet PA, Svansson V, Tozaki T, Wilkinson-White L, Penedo MC, Rieder S, Leeb T.
(2012).
Mutations in MITF and PAX3 cause “splashed white” and other white spotting phenotypes in horses.
PLoS Genet, 8(4), e1002653.
https://doi.org/10.1371/journal.pgen.1002653 Publication
Researcher Affiliations
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
MeSH Terms
- Animals
- Base Sequence
- Chromosome Mapping
- Color
- Genetic Linkage
- Genome
- Genome-Wide Association Study
- Hair Color
- Horses / genetics
- Lod Score
- Melanocytes / metabolism
- Microphthalmia-Associated Transcription Factor / genetics
- Microphthalmia-Associated Transcription Factor / metabolism
- Molecular Sequence Data
- Mutation
- Paired Box Transcription Factors / genetics
- Phenotype
- Pigmentation / genetics
- Promoter Regions, Genetic
Conflict of Interest Statement
The authors have declared that no competing interests exist.
References
This article includes 32 references
- Thomas AJ, Erickson CA. The making of a melanocyte: the specification of melanoblasts from the neural crest.. Pigment Cell Melanoma Res 2008 Dec;21(6):598-610.
- Geissler EN, Ryan MA, Housman DE. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene.. Cell 1988 Oct 7;55(1):185-92.
- Hodgkinson CA, Moore KJ, Nakayama A, Steingru00edmsson E, Copeland NG, Jenkins NA, Arnheiter H. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein.. Cell 1993 Jul 30;74(2):395-404.
- Silver DL, Hou L, Somerville R, Young ME, Apte SS, Pavan WJ. The secreted metalloprotease ADAMTS20 is required for melanoblast survival.. PLoS Genet 2008 Feb 29;4(2):e1000003.
- Thomas AJ, Erickson CA. FOXD3 regulates the lineage switch between neural crest-derived glial cells and pigment cells by repressing MITF through a non-canonical mechanism.. Development 2009 Jun;136(11):1849-58.
- Scholl FA, Kamarashev J, Murmann OV, Geertsen R, Dummer R, Schu00e4fer BW. PAX3 is expressed in human melanomas and contributes to tumor cell survival.. Cancer Res 2001 Feb 1;61(3):823-6.
- Baxter LL, Hou L, Loftus SK, Pavan WJ. Spotlight on spotted mice: a review of white spotting mouse mutants and associated human pigmentation disorders.. Pigment Cell Res 2004 Jun;17(3):215-24.
- Rieder S, Hagger C, Obexer-Ruff G, Leeb T, Poncet PA. Genetic analysis of white facial and leg markings in the Swiss Franches-Montagnes Horse Breed.. J Hered 2008 Mar-Apr;99(2):130-6.
- Sponenberg DP. Equine color genetics, 3rd edition. Ames: Wiley-Blackwell; 2009. 277
- Brooks SA, Bailey E. Exon skipping in the KIT gene causes a Sabino spotting pattern in horses.. Mamm Genome 2005 Nov;16(11):893-902.
- Brooks SA, Lear TL, Adelson DL, Bailey E. A chromosome inversion near the KIT gene and the Tobiano spotting pattern in horses.. Cytogenet Genome Res 2007;119(3-4):225-30.
- Haase B, Brooks SA, Schlumbaum A, Azor PJ, Bailey E, Alaeddine F, Mevissen M, Burger D, Poncet PA, Rieder S, Leeb T. Allelic heterogeneity at the equine KIT locus in dominant white (W) horses.. PLoS Genet 2007 Nov;3(11):e195.
- Haase B, Brooks SA, Tozaki T, Burger D, Poncet PA, Rieder S, Hasegawa T, Penedo C, Leeb T. Seven novel KIT mutations in horses with white coat colour phenotypes.. Anim Genet 2009 Oct;40(5):623-9.
- Haase B, Rieder S, Tozaki T, Hasegawa T, Penedo MC, Jude R, Leeb T. Five novel KIT mutations in horses with white coat colour phenotypes.. Anim Genet 2011 Jun;42(3):337-9.
- Metallinos DL, Bowling AT, Rine J. A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung disease.. Mamm Genome 1998 Jun;9(6):426-31.
- Santschi EM, Purdy AK, Valberg SJ, Vrotsos PD, Kaese H, Mickelson JR. Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses.. Mamm Genome 1998 Apr;9(4):306-9.
- Yang GC, Croaker D, Zhang AL, Manglick P, Cartmill T, Cass D. A dinucleotide mutation in the endothelin-B receptor gene is associated with lethal white foal syndrome (LWFS); a horse variant of Hirschsprung disease.. Hum Mol Genet 1998 Jun;7(6):1047-52.
- Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N. Review and update of mutations causing Waardenburg syndrome.. Hum Mutat 2010 Apr;31(4):391-406.
- Tachibana M, Kobayashi Y, Matsushima Y. Mouse models for four types of Waardenburg syndrome.. Pigment Cell Res 2003 Oct;16(5):448-54.
- Xu HE, Rould MA, Xu W, Epstein JA, Maas RL, Pabo CO. Crystal structure of the human Pax6 paired domain-DNA complex reveals specific roles for the linker region and carboxy-terminal subdomain in DNA binding.. Genes Dev 1999 May 15;13(10):1263-75.
- Fuse N, Yasumoto K, Suzuki H, Takahashi K, Shibahara S. Identification of a melanocyte-type promoter of the microphthalmia-associated transcription factor gene.. Biochem Biophys Res Commun 1996 Feb 27;219(3):702-7.
- Bondurand N, Pingault V, Goerich DE, Lemort N, Sock E, Le Caignec C, Wegner M, Goossens M. Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome.. Hum Mol Genet 2000 Aug 12;9(13):1907-17.
- Hallsson JH, Haflidadu00f3ttir BS, Schepsky A, Arnheiter H, Steingru00edmsson E. Evolutionary sequence comparison of the Mitf gene reveals novel conserved domains.. Pigment Cell Res 2007 Jun;20(3):185-200.
- Karlsson EK, Baranowska I, Wade CM, Salmon Hillbertz NH, Zody MC, Anderson N, Biagi TM, Patterson N, Pielberg GR, Kulbokas EJ 3rd, Comstock KE, Keller ET, Mesirov JP, von Euler H, Ku00e4mpe O, Hedhammar A, Lander ES, Andersson G, Andersson L, Lindblad-Toh K. Efficient mapping of mendelian traits in dogs through genome-wide association.. Nat Genet 2007 Nov;39(11):1321-8.
- Smith SD, Kelley PM, Kenyon JB, Hoover D. Tietz syndrome (hypopigmentation/deafness) caused by mutation of MITF.. J Med Genet 2000 Jun;37(6):446-8.
- Epstein DJ, Vekemans M, Gros P. Splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3.. Cell 1991 Nov 15;67(4):767-74.
- Hodgkinson CA, Moore KJ, Nakayama A, Steingru00edmsson E, Copeland NG, Jenkins NA, Arnheiter H. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein.. Cell 1993 Jul 30;74(2):395-404.
- Woolf CM. Common white facial markings in bay and chestnut Arabian horses and their hybrids.. J Hered 1991 Mar-Apr;82(2):167-9.
- Steingru00edmsson E, Copeland NG, Jenkins NA. Melanocytes and the microphthalmia transcription factor network.. Annu Rev Genet 2004;38:365-411.
- Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: a tool set for whole-genome association and population-based linkage analyses.. Am J Hum Genet 2007 Sep;81(3):559-75.
- Abecasis GR, Cherny SS, Cookson WO, Cardon LR. Merlin--rapid analysis of dense genetic maps using sparse gene flow trees.. Nat Genet 2002 Jan;30(1):97-101.
- Wilkinson-White L, Gamsjaeger R, Dastmalchi S, Wienert B, Stokes PH, Crossley M, Mackay JP, Matthews JM. Structural basis of simultaneous recruitment of the transcriptional regulators LMO2 and FOG1/ZFPM1 by the transcription factor GATA1.. Proc Natl Acad Sci U S A 2011 Aug 30;108(35):14443-8.
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