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

In other species: taurine cattle , indicine cattle (zebu)

Categories: Pigmentation phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 604204 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2008

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

Species-specific symbol: G, G2, G3

Species-specific description: Horses are born with normal pigmentation, but gradually lose their pigmentation as they age, until, typically 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 (see OMIA:002231-9796 : Melanoma, generic in Equus caballus)

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).
Nowacka-Woszuk et al. (2021) assessed "the usefulness of droplet digital PCR (ddPCR) in precise genotyping of equine STX17 4.6-kb duplication ... ." Genotyping of 75 horses representing various breeds "revealed that the tested individuals had copy numbers of the 4.6-kb STX17 fragment equal to 6, 4, or 2 for the GG, Gg, and gg gray mutation genotypes, respectively. [Their] results thus suggest that the equine graying with age mutation is a triplication." The authors suggest that "further studies of wider range material are needed to fully understand the molecular structure of the graying with age causative mutation within the equine STX17 gene."
Rubin et al. (2024) "demonstrate the presence of two different Grey alleles, G2 carrying two tandem copies of the duplicated sequence and G3 carrying three. The latter is by far the most common allele, probably due to strong selection for the striking white phenotype. [Their] results reveal a remarkable dosage effect where the G3 allele is associated with fast greying and high incidence of melanoma whereas G2 is associated with slow greying and low incidence of melanoma. The copy number expansion transforms a weak enhancer to a strong melanocyte-specific enhancer that underlies hair greying (G2 and G3) and a drastically elevated risk of melanoma (G3 only)."

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.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
438 Coat colour, grey/gray (slow greying) STX17 G2 repeat variation Naturally occurring variant EquCab3 25 NC_009168.3:g.6625295_6629872dup two tandom copies of a 4.6kb intronic region in STX17, which increase the expression of both STX17 and a neighbouring gene NR4A3 2008 18641652
1732 Coat colour, grey/gray (fast greying) STX17 G3 repeat variation Naturally occurring variant EquCAb3 25 NC_009168.3:g.6625295_6629872[3] three tandom copies of a 4.6kb intronic region in STX17 which increase the expression of both syntaxin-17 and a neighbouring gene NR4A3 2024 39209879

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2024). OMIA:001356-9796: Online Mendelian Inheritance in Animals (OMIA) [dataset]. https://omia.org/. https://doi.org/10.25910/2AMR-PV70

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.

2024 Andersson, L. :
White horses - non-coding sequences drive premature hair greying and predisposition to melanoma. Ups J Med Sci 129, 2024. Pubmed reference: 38571883. DOI: 10.48101/ujms.v129.10626.
Brodesser, D.M., Kummer, S., Eichberger, J.A., Schlangen, K., Corteggio, A., Borzacchiello, G., Bertram, C.A., Brandt, S., Pratscher, B. :
Deregulation of metalloproteinase expression in gray horse melanoma ex vivo and in vitro. Cells 13:956, 2024. Pubmed reference: 38891088. DOI: 10.3390/cells13110956.
De Coster, T., Zhao, Y., Tšuiko, O., Demyda-Peyrás, S., Van Soom, A., Vermeesch, J.R., Smits, K. :
Genome-wide equine preimplantation genetic testing enabled by simultaneous haplotyping and copy number detection. Sci Rep 14:2003, 2024. Pubmed reference: 38263320. DOI: 10.1038/s41598-023-48103-7.
Rubin, C.J., Hodge, M., Naboulsi, R., Beckman, M., Bellone, R.R., Kallenberg, A., J'Usrey, S., Ohmura, H., Seki, K., Furukawa, R., Ohnuma, A., Davis, B.W., Tozaki, T., Lindgren, G., Andersson, L. :
An intronic copy number variation in Syntaxin 17 determines speed of greying and melanoma incidence in Grey horses. Nat Commun 15:7510, 2024. Pubmed reference: 39209879. DOI: 10.1038/s41467-024-51898-2.
2023 Haughan, J., Ortved, K.F., Robinson, M.A. :
Administration and detection of gene therapy in horses: A systematic review. Drug Test Anal 15:143-162, 2023. Pubmed reference: 36269665. DOI: 10.1002/dta.3394.
2022 Druml, T., Brem, G., Horna, M., Ricard, A., Grilz-Seger, G. :
DPF3, a putative candidate gene for melanoma etiopathogenesis in gray horses. J Equine Vet Sci 108:103797, 2022. Pubmed reference: 34801788. DOI: 10.1016/j.jevs.2021.103797.
2021 Nowacka-Woszuk, J., Mackowski, M., Mantaj, W., Stefaniuk-Szmukier, M., Cieslak, J. :
Equine STX17 intronic triplication confirmed by droplet digital PCR analysis of its breakpoints. Anim Genet 52:567-68, 2021. Pubmed reference: 33939848. DOI: 10.1111/age.13073.
Nowacka-Woszuk, J., Mackowski, M., Stefaniuk-Szmukier, M., Cieslak, J. :
The equine graying with age mutation of the STX17 gene: A copy number study using droplet digital PCR reveals a new pattern. Anim Genet 52:223-227, 2021. Pubmed reference: 33550611. DOI: 10.1111/age.13044.
2019 MacKay, R.J. :
Treatment options for melanoma of gray horses. Vet Clin North Am Equine Pract 35:311-325, 2019. Pubmed reference: 31279435. DOI: 10.1016/j.cveq.2019.04.003.
Sánchez-Guerrero, M.J., Solé, M., Azor, P.J., Sölkner, J., Valera, M. :
Genetic and environmental risk factors for vitiligo and melanoma in Pura Raza Español horses. Equine Vet J 51:606-611, 2019. Pubmed reference: 30624804. DOI: 10.1111/evj.13067.
Wong, K., van der Weyden, L., Schott, C.R., Foote, A., Constantino-Casas, F., Smith, S., Dobson, J.M., Murchison, E.P., Wu, H., Yeh, I., Fullen, D.R., Joseph, N., Bastian, B.C., Patel, R.M., Martincorena, I., Robles-Espinoza, C.D., Iyer, V., Kuijjer, M.L., Arends, M.J., Brenn, T., Harms, P.W., Wood, G.A., Adams, D.J. :
Cross-species genomic landscape comparison of human mucosal melanoma with canine oral and equine melanoma. Nat Commun 10:353, 2019. Pubmed reference: 30664638. DOI: 10.1038/s41467-018-08081-1.
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.
Metcalfe, L.V., O'Brien, P.J., Papakonstantinou, S., Cahalan, S.D., McAllister, H., Duggan, V.E. :
Malignant melanoma in a grey horse: case presentation and review of equine melanoma treatment options. Ir Vet J 66:22, 2013. Pubmed reference: 24196087. DOI: 10.1186/2046-0481-66-22.
Moore, J.S., Shaw, C., Shaw, E., Buechner-Maxwell, V., Scarratt, W.K., Crisman, M., Furr, M., Robertson, J. :
Melanoma in horses: Current perspectives. Equine Veterinary Education 25:144-151, 2013. DOI: doi.org/10.1111/j.2042-3292.2011.00368.x.
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 50:56-65, 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 27:1201-8, 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., 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.
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.
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.

Edit History


  • Created by Frank Nicholas on 22 Jul 2008
  • Changed by Frank Nicholas on 07 Sep 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 22 Aug 2012
  • Changed by Frank Nicholas on 18 Dec 2012
  • Changed by Frank Nicholas on 22 May 2013
  • Changed by Frank Nicholas on 05 Aug 2013
  • Changed by Frank Nicholas on 12 Aug 2013
  • Changed by Imke Tammen2 on 08 Apr 2021
  • Changed by Imke Tammen2 on 12 Apr 2021
  • Changed by Imke Tammen2 on 24 Nov 2021
  • Changed by Imke Tammen2 on 18 Apr 2023
  • Changed by Imke Tammen2 on 02 Sep 2024