OMIA 001356-9796 : Coat colour, grey/gray in Equus caballus

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Dominant

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2008

Species-specific name: Gray; Grey; Greying with age

Species-specific symbol: G

Species-specific description: Horses are born with normal pigmentation, but gradually lose their pigmentation as they age, until, at around 6-8 years old, they become white, while retaining dark skin pigmentation. Included with this phenotype is a relatively high incidence of dermal melanomas, and an associated decrease in life expectancy.

History: As summarised by Pielberg et al. (2008), white horses have been favoured by humans for hundreds of years.

Mapping: Rosengren Pielberg et al. (2005) fine-mapped this locus to a region less than 3 cM between two genes (NANS and ABCA1) on ECA25. Comparative mapping with humans and mice suggested no obvious candidate genes in this region, implying that this coat colour is due to a mutation in a gene not yet identified.

Molecular basis: Rosengren Pielberg et al. (2008) presented convincing evidence that this classic phenotype is due to a 4.6kb intronic duplication in the gene for syntaxin-17 (STX17). This duplication appears to increase the expression of both syntaxin-17 and a neighbouring gene NR4A3, which encodes nuclear receptor subfamily 4, group A, member 3. Whilst the details are still to be elucidated, Pielberg et al. (2008) present circumstantial evidence that overexpression of one or both of these two genes leads to a hyperproliferation of hair-follicle melanocytes, leading to a gradual depletion of progenitor stem cells, and hence to a gradual loss of hair pigmentation as the animal ages. At the same time, the overexpression of one or both of these genes leads to a proliferation of dermal melanocytes in glabrous skin (skin that naturally lacks hair), which predisposes to melanoma development.

Curik et al. (2013) provided evidence that "the STX17 mutation explains to a large extent the moderate to high genetic correlations among [melanoma grade, grey level, vitiligo grade, and speckling grade] . . . , providing an example of strong pleiotropic effects caused by a single gene". Leeb (2013) provides a very informative summary of the results of Curik et al. (2013).

Genetic testing: Since exactly the same mutation is completely associated with the grey/gray phenotype in more than 850 horses from numerous breeds (Rosengren Pielberg et al., 2008), it is very likely that a single DNA test will suffice to detect virtually all occurrences of the grey/gray allele.

Kavar et al. (2012) provide details of a robust DNA test.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
STX17 syntaxin 17 Equus caballus 25 NC_009168.3 (6574696..6638560) STX17 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Coat colour, grey/gray STX17 duplication a 4.6kb intronic duplication in the gene for syntaxin-17 (STX17). This duplication appears to increase the expression of both syntaxin-17 and a neighbouring gene NR4A3, 2008 18641652

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2015 Gao, K.X., Chen, N.B., Liu, W.J., Li, R., Lan, X.Y., Chen, H., Lei, C.Z., Dang, R.H. :
Frequency of gray coat color in native Chinese horse breeds. Genet Mol Res 14:14144-50, 2015. Pubmed reference: 26535731. DOI: 10.4238/2015.October.29.36.
2013 Curik, I., Druml, T., Seltenhammer, M., Sundström, E., Pielberg, G.R., Andersson, L., Sölkner, J. :
Complex inheritance of melanoma and pigmentation of coat and skin in Grey horses. PLoS Genet 9:e1003248, 2013. Pubmed reference: 23408897. DOI: 10.1371/journal.pgen.1003248.
Leeb, T. :
The Spanish Riding School and the Haute Ecole of complex trait genetics. Pigment Cell Melanoma Res 26:439-40, 2013. Pubmed reference: 23923822. DOI: 10.1111/pcmr.12116.
Seltenhammer, M.H., Sundström, E., Meisslitzer-Ruppitsch, C., Cejka, P., Kosiuk, J., Neumüller, J., Almeder, M., Majdic, O., Steinberger, P., Losert, U.M., Stöckl, J., Andersson, L., Sölkner, J., Vetterlein, M., Golovko, A. :
Establishment and characterization of a primary and a metastatic melanoma cell line from Grey horses. In Vitro Cell Dev Biol Anim :, 2013. Pubmed reference: 23982913. DOI: 10.1007/s11626-013-9678-1.
Teixeira, R.B., Rendahl, A.K., Anderson, S.M., Mickelson, J.R., Sigler, D., Buchanan, B.R., Coleman, R.J., McCue, M.E. :
Coat Color Genotypes and Risk and Severity of Melanoma in Gray Quarter Horses. J Vet Intern Med :, 2013. Pubmed reference: 23875712. DOI: 10.1111/jvim.12133.
2012 Kavar, T., Ceh, E., Dovč, P. :
A simplified PCR-based method for detection of gray coat color allele in horse. Mol Cell Probes 26:256-8, 2012. Pubmed reference: 22433981. DOI: 10.1016/j.mcp.2012.02.006.
Sundström, E., Imsland, F., Mikko, S., Wade, C., Sigurdsson, S., Pielberg, G.R., Golovko, A., Curik, I., Seltenhammer, M.H., Sölkner, J., Lindblad-Toh, K., Andersson, L. :
Copy number expansion of the STX17 duplication in melanoma tissue from Grey horses. BMC Genomics 13:365, 2012. Pubmed reference: 22857264. DOI: 10.1186/1471-2164-13-365.
Sundström, E., Komisarczuk, A.Z., Jiang, L., Golovko, A., Navratilova, P., Rinkwitz, S., Becker, T.S., Andersson, L. :
Identification of a melanocyte-specific, microphthalmia-associated transcription factor-dependent regulatory element in the intronic duplication causing hair greying and melanoma in horses. Pigment Cell Melanoma Res 25:28-36, 2012. Pubmed reference: 21883983. DOI: 10.1111/j.1755-148X.2011.00902.x.
2010 Bellone, RR. :
Pleiotropic effects of pigmentation genes in horses. Anim Genet 41 Suppl 2:100-10, 2010. Pubmed reference: 21070283. DOI: 10.1111/j.1365-2052.2010.02116.x.
Li, B., He, XL., Zhao, YP., Wang, XJ., Manglai, D., Zhang, YR. :
[Molecular basis and applicability in equine color genetics]. Yi Chuan 32:1133-40, 2010. Pubmed reference: 21513164.
2009 Rieder, S. :
Molecular tests for coat colours in horses. J Anim Breed Genet 126:415-24, 2009. Pubmed reference: 19912415. DOI: 10.1111/j.1439-0388.2009.00832.x.
2008 Rosengren Pielberg, G., Golovko, A., Sundstrom, E., Curik, I., Lennartsson, J., Seltenhammer, M.H., Druml, T., Binns, M., Fitzsimmons, C., Lindgren, G., Sandberg, K., Baumung, R., Vetterlein, M., Stromberg, S., Grabherr, M., Wade, C., Lindblad-Toh, K., Ponten, F., Heldin, C-H., Solkner, J., Andersson, L. :
A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse Nature Genetics 40:1004-1009, 2008. Pubmed reference: 18641652. DOI: 10.1038/ng.185.
2005 Pielberg, G., Mikko, S., Sandberg, K., Andersson, L. :
Comparative linkage mapping of the Grey coat colour gene in horses. Anim Genet 36:390-5, 2005. Pubmed reference: 16167981. DOI: 10.1111/j.1365-2052.2005.01334.x.
2004 Seltenhammer, MH., Heere-Ress, E., Brandt, S., Druml, T., Jansen, B., Pehamberger, H., Niebauer, GW. :
Comparative histopathology of grey-horse-melanoma and human malignant melanoma. Pigment Cell Res 17:674-81, 2004. Pubmed reference: 15541026. DOI: 10.1111/j.1600-0749.2004.00192.x.
2003 Seltenhammer, M.H., Simhofer, H., Scherzer, S., Zechner, R., Curik, I., Sölkner, J., Brandt, S.M., Jansen, B., Pehamberger, H., Eisenmenger, E. :
Equine melanoma in a population of 296 grey Lipizzaner horses. Equine Vet J 35:153-7, 2003. Pubmed reference: 12638791.
2002 Henner, J., Poncet, P.A., Guerin, G., Hagger, C., Stranzinger, G., Rieder, S. :
Genetic mapping of the (G)-locus, responsible for the coat color phenotype "progressive greying with age" in horses (Equus caballus) Mammalian Genome 13:535-537, 2002. Pubmed reference: 12370784. DOI: 10.1007/s00335-002-2174-7.
Locke, M.M., Penedo, M.C.T., Bricker, S.J., Millon, L.V., Murray, J.D. :
Linkage of the grey coat colour locus to microsatellites on horse chromosome 25 Animal Genetics 33:329-337, 2002. Pubmed reference: 12354140.
Swinburne, J.E., Hopkins, A., Binns, M.M. :
Assignment of the horse grey coat colour gene to ECA25 using whole genome scanning Animal Genetics 33:338-342, 2002. Pubmed reference: 12354141.
2001 Heinzerling, LM., Feige, K., Rieder, S., Akens, MK., Dummer, R., Stranzinger, G., Moelling, K. :
Tumor regression induced by intratumoral injection of DNA coding for human interleukin 12 into melanoma metastases in gray horses. J Mol Med 78:692-702, 2001. Pubmed reference: 11434722.
Patterson-Kane, JC., Sanchez, LC., Uhl, EW., Edens, LM. :
Disseminated metastatic intramedullary melanoma in an aged grey horse. J Comp Pathol 125:204-7, 2001. Pubmed reference: 11578137. DOI: 10.1053/jcpa.2001.0481.
2000 Fleury, C., Bérard, F., Balme, B., Thomas, L. :
The study of cutaneous melanomas in Camargue-type gray-skinned horses (1): clinical-pathological characterization. Pigment Cell Res 13:39-46, 2000. Pubmed reference: 10761995.
Fleury, C., Bérard, F., Leblond, A., Faure, C., Ganem, N., Thomas, L. :
The study of cutaneous melanomas in Camargue-type gray-skinned horses (2): epidemiological survey. Pigment Cell Res 13:47-51, 2000. Pubmed reference: 10761996.
1993 Ohmuro, K., Okada, K., Satoh, A., Murakami, K., Satake, S., Asahina, M., Numakunai, S., Ohshima, K. :
Morphogenesis of compound melanosomes in melanoma cells of a gray horse. J Vet Med Sci 55:677-80, 1993. Pubmed reference: 8399754.
1977 Gebhart, W., Niebauer, GW. :
[Comparative investigations of depigmented and melanomatous lesions in gray horses of the lipizzaner breed (author's transl)] Arch Dermatol Res 259:29-42, 1977. Pubmed reference: 900991.
1933 McFadyean, J. :
Equine melanomatosis Journal of Comparative Pathology and Therapy 46:186-204, 1933.

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