Mutations in MITF and PAX3 cause “splashed white” and other white spotting phenotypes in horses
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Changes in neural crest-related genes underlie the evolution of tameness during cat domestication.
“Taken together, we propose that changes in these neural crest-related genes underlie the evolution of tameness during cat domestication, in agreement with analyses of other domesticated genomes (56)(57)(58).”
From Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication (2014) · cites this paper as [56]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Merlin—rapid analysis of dense genetic maps using sparse gene flow trees
Abecasis, G. R., Cherny, S. S., Cookson, W., & Cardon, L. R. (2001) · Nature Genetics · doi:10.1038/ng786 · Cited by 3,323 · see citing works
The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene
Geissler, E. N., Ryan, M. A., & Housman, D. E. (1988) · Cell · doi:10.1016/0092-8674(88)90020-7 · Cited by 1,287 · see citing works
Hodgkinson, C. A., Moore, K. J., Nakayama, A., Steingrı́msson, E., Copeland, N. G., Jenkins, N. A., & Arnheiter, H. (1993) · Cell · doi:10.1016/0092-8674(93)90429-t · Cited by 1,092 · see citing works
Melanocytes and theMicrophthalmiaTranscription Factor Network
Steingrı́msson, E., Copeland, N. G., & Jenkins, N. A. (2004) · Annual Review of Genetics · doi:10.1146/annurev.genet.38.072902.092717 · Cited by 762 · see citing works
Epstein, D. J., Vekemans, M. J. J., & Gros, P. (1991) · Cell · doi:10.1016/0092-8674(91)90071-6 · Cited by 670 · see citing works
Review and update of mutations causing Waardenburg syndrome
Pingault, V., Ente, D., Moal, F., Goossens, M., Marlin, S., & Bondurand, N. (2010) · Human Mutation · doi:10.1002/humu.21211 · Cited by 596 · see citing works
Efficient mapping of mendelian traits in dogs through genome-wide association
Karlsson, E. K., Baranowska, I., Wade, C. M., Hillbertz, N. S., Zody, M. C., Anderson, N., Biagi, T., Patterson, N. J., Pielberg, G., Kulbokas, E. J., et al. (2007) · Nature Genetics · doi:10.1038/ng.2007.10 · Cited by 560 · see citing works
Interaction among SOX10, PAX3 and MITF, three genes altered in Waardenburg syndrome
Bondurand, N. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.13.1907 · Cited by 466 · see citing works
Xu, H. E., Rould, M. A., Xu, W., Epstein, J. A., Maas, R. L., & Pabo, C. O. (1999) · Genes & Development · doi:10.1101/gad.13.10.1263 · Cited by 311 · see citing works
The making of a melanocyte: the specification of melanoblasts from the neural crest
Thomas, A. J., & Erickson, C. A. (2008) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2008.00506.x · Cited by 253 · see citing works
Metallinos, D. L., & Rine, J. (1998) · Mammalian Genome · doi:10.1007/s003359900790 · Cited by 184 · see citing works
Thomas, A. J., & Erickson, C. A. (2009) · Development · doi:10.1242/dev.031989 · Cited by 176 · see citing works
Endothelin receptor B polymorphism associated with lethal white foal syndrome in horses
Santschi, E. M., Purdy, A. K., Valberg, S. J., et al. (1998) · Mammalian Genome · doi:10.1007/s003359900754 · Cited by 158 · see citing works
Tietz syndrome (hypopigmentation/deafness) caused by mutation ofMITF : Figure 1
Smith, S. D., Kelley, P. M., Kenyon, J. B., et al. (2000) · Journal of Medical Genetics · doi:10.1136/jmg.37.6.446 · Cited by 155 · see citing works
Allelic Heterogeneity at the Equine KIT Locus in Dominant White (W) Horses
Haase, B., Brooks, S. A., Schlumbaum, A., Azor, P. J., Bailey, E., Alaeddine, F., Mevissen, M., Burger, D., Poncet, P.-A., Rieder, S., et al. (2007) · PLoS Genetics · doi:10.1371/journal.pgen.0030195 · Cited by 143 · see citing works
Self-citationThe Secreted Metalloprotease ADAMTS20 Is Required for Melanoblast Survival
Silver, D. L., Hou, L., Somerville, R. P. T., Young, M. E., Apte, S., & Pavan, W. J. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000003 · Cited by 132 · see citing works
Fuse, N., Yasumoto, K., Suzuki, H., Takahashi, K., & Shibahara, S. (1996) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1996.0298 · Cited by 128 · see citing works
PAX3 is expressed in human melanomas and contributes to tumor cell survival.
Scholl, F. A., Kamarashev, J. A., Murmann, O. V., et al. (2001) · PubMed · Cited by 122 · see citing works
Baxter, L. L., Hou, L., Loftus, S. K., & Pavan, W. J. (2004) · Pigment Cell Research · doi:10.1111/j.1600-0749.2004.00147.x · Cited by 122 · see citing works
Exon skipping in the KIT gene causes a Sabino spotting pattern in horses
Brooks, S. A., & Bailey, E. (2005) · Mammalian Genome · doi:10.1007/s00335-005-2472-y · Cited by 119 · see citing works
Self-citationSeven novel KIT mutations in horses with white coat colour phenotypes
Haase, B., Brooks, S. A., Tozaki, T., Burger, D., Poncet, P. A., Rieder, S., Hasegawa, T., Penedo, C., & Leeb, T. (2009) · Animal Genetics · doi:10.1111/j.1365-2052.2009.01893.x · Cited by 111 · see citing works
Self-citationYang, G. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.6.1047 · Cited by 105 · see citing works
A chromosome inversion near the KIT gene and the Tobiano spotting pattern in horses
Brooks, S. A., Lear, T. L., Adelson, D. L., & Bailey, E. (2007) · Cytogenetic and Genome Research · doi:10.1159/000112065 · Cited by 101 · see citing works
Self-citationMouse Models for Four Types of Waardenburg Syndrome
Tachibana, M., Kobayashi, Y., & Matsushima, Y. (2003) · Pigment Cell Research · doi:10.1034/j.1600-0749.2003.00066.x · Cited by 100 · see citing works
Wilkinson‐White, L. E., Gamsjaeger, R., Dastmalchi, S., Wienert, B., Stokes, P. H., Crossley, M., Mackay, J. P., & Matthews, J. M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105898108 · Cited by 52 · see citing works
Self-citationEvolutionary sequence comparison of the Mitf gene reveals novel conserved domains
Hallsson, J. H., Haflidadóttir, B. S., Schepsky, A., Arnheiter, H., & Steingrı́msson, E. (2007) · Pigment Cell Research · doi:10.1111/j.1600-0749.2007.00373.x · Cited by 40 · see citing works
Five novel KIT mutations in horses with white coat colour phenotypes
Haase, B., Rieder, S., Tozaki, T., et al. (2011) · Animal Genetics · doi:10.1111/j.1365-2052.2011.02173.x · Cited by 35 · see citing works
Self-citationGenetic Analysis of White Facial and Leg Markings in the Swiss Franches-Montagnes Horse Breed
Rieder, S., Hagger, C., Obexer‐Ruff, G., et al. (2008) · Journal of Heredity · doi:10.1093/jhered/esm115 · Cited by 23 · see citing works
Self-citationCommon White Facial Markings in Bay and Chestnut Arabian Horses and Their Hybrids
Woolf, C. M. (1991) · Journal of Heredity · doi:10.1093/oxfordjournals.jhered.a111053 · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [9]Sponenberg DP 2009 Equine color genetics, 3rd edition Ames Wiley-Blackwell 277
- [27]Hodgkinson CA Moore KJ Nakayama A Steingrímsson E Copeland NG 1993 Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 74 395 404 8343963
Cited by
Sorted by citations
Wilkins, A. S., Wrangham, R. W., & Fitch, W. T. (2014) · Genetics · doi:10.1534/genetics.114.165423 · Cited by 751 · see citing works
The melanocyte lineage in development and disease
Mort, R. L., Jackson, I. J., & Patton, E. E. (2015) · Development · doi:10.1242/dev.106567 · Cited by 416 · see citing works
Montague, M. J., Li, G., Gandolfi, B., Khan, R., Aken, B. L., Searle, S. M. J., Minx, P., Hillier, L. W., Koboldt, D. C., Davis, B. W., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1410083111 · Cited by 340 · see citing works
Pleiotropic effects of coat colour-associated mutations in humans, mice and other mammals
Reissmann, M., & Ludwig, A. (2013) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2013.03.014 · Cited by 149 · see citing works
Jivanji, S., Worth, G., Lopdell, T. J., Yeates, A., Couldrey, C., Reynolds, E., Tiplady, K., McNaughton, L., Johnson, T. J. J., Davis, S. R., et al. (2019) · Genetics Selection Evolution · doi:10.1186/s12711-019-0506-2 · Cited by 41 · see citing works
- Authors
- Hauswirth, R., Haase, B., Blatter, M., Brooks, S. A., Burger, D., Drögemüller, C., Gerber, V., Henke, D., Janda, J., Jude, R., Magdesian, K. G., Matthews, J. M., Poncet, P.-A., Svansson, V., Tozaki, T., Wilkinson-White, L., Penedo, M. C. T., Rieder, S., & Leeb, T.
- Affiliations
- University of Bern (CH)
- The University of Sydney (AU)
- Cornell University (US)
- University of California, Davis (US)
- University of Iceland (IS)
- Laboratory of Racing Chemistry (JP)
- Corresponding author
- Leeb, Tosso
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-04-12
- Volume
- 8
- Issue
- 4
- Pages
- e1002653
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3325211
- OpenAlex
- W2097062114
- Cited by
- 170
- References
- 30
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 10 · 2023: 11 · 2022: 13 · 2021: 9 · 2020: 15 · 2019: 18 · 2018: 11 · 2017: 19 · 2016: 9 · 2015: 17 · 2014: 12 · 2013: 8
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-08-02)
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Open Access CRIS of the University of Bern
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (133034)
- Université de Genève
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Health Sciences › Veterinary › Equine › Veterinary Equine Medical Research
- Keywords
- white spotting, MITF, Pax3, horses, Quarter Horse, melanocyte development, missense mutations, promoter insertion, genome-wide linkage analysis, genome-wide association study, endothelin B receptor, KIT, deafness, coat color inheritance
- MeSH terms
- Animals, Base Sequence, Chromosome Mapping, Color, Hair Color, Horses, Genetic Linkage, Lod Score, Melanocytes, Molecular Sequence Data, Mutation, Phenotype, Pigmentation, Promoter Regions, Genetic, Genome, Microphthalmia-Associated Transcription Factor, Paired Box Transcription Factors, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
