OMIA 000214-9796 : Coat colour, white spotting in Equus caballus

In other species: domestic cat , dog , cattle , water buffalo , domestic guinea pig

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 193510 , 103500

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Semi-Dominant

Considered a defect: unknown

Key variant known: yes

Year key variant first reported: 2012

Cross-species summary: Variable degree of white spotting ranging from tiny white spots up to completely white animals. The absence of pigment is caused by the absence of skin melanocytes ("leucism"), not by failure in the biochemical reactions required for pigment synthesis.

Species-specific name: Splashed white, macchiato

Species-specific description: Currently (in 2016), among domesticated animals the horse is the species with the highest number of known genetic variants that lead to white spotting phenotypes. Related coat colour phenotypes are caused by variants in the EDNRB, KIT, MITF, PAX3 and TPRM1 genes. Combinations of multiple variants in these gene can lead to more pronounced coat colour phenotypes. Variants in MITF can lead to a variable degree of white spotting. The splashed white phenotype in horses is most frequently due to variants in the MITF gene, but may also be caused by variants in the PAX3 gene. As described by Hauswirth et al. (2012), "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."

Inheritance: Animals with the typical splashed white phenotype normally have only one copy of the mutant allele(s). Homozygosity for the mutant alleles results in either embryonic lethality or more pronounced depigmentation phenotypes.

Molecular basis: Hauswirth et al. (2012) reported a non-coding regulatory 10 bp insertion into the melanocyte-specific promoter of the MITF gene (ECA16:g.20,117,302Tdelins11; "SW1"), which disrupts a PAX3 binding site. This allele is apparently several hundred years old and can be found in many different breeds segregating for the splashed white phenotype, such as e.g. American Paint Horses, Icelandic Horses, Miniature Horses, Quarter Horses, Shetland Ponies, Thoroughbreds, and Trakehner. Horses heterozygous for the SW1 allele exhibit the splashed white phenotype. Horses homozygous for SW1 are viable and often show very pronounced spotting patterns, which also involve depigmentation of parts of the trunk.

Hauswirth et al. (2012) reported a frameshift mutation in exon 5 of the MITF gene (c.837_841delGTGTC; p.C280fs*20; "SW3"), which also causes a splashed white phenotype. This variant appears to be very young and was exclusively encountered in a Quarter Horse mare and her American Paint Horse registered foal. It is assumed that the "SW3" allele leads to embryonic lethality in the homozygous state (Hauswirth et al. 2012).

Hauswirth et al. (2012) furthermore reported a reported "a de novo missense mutation in exon 6 of the MITF gene . . . (c.929A>G; )" in a Franches-Montagnes stallion as causing the newly-described macchiato phenotype. If the melanocyte-specific transcript MITF-M is considered (XM_005600318.1), this variant should be termed c.629G>A or p.Asn210Ser. The amino acid exchange affects the conserved bHLH DNA binding domain and leads to weaker binding of the mutant MITF protein to target DNA. This variant thus has a more pronounced phenotypic effect than the SW1 and SW3 variants, probably due to a dominant-negative interaction of mutant MITF with the wildtype protein.

Haase et al. (2013) provided evidence that additional non-coding regulatory variants at the KIT and MITF loci contribute to the genetic control of white markings in horses. However, the exact variants and their quantitative effect sizes could not be resolved as they act together in functional haplotypes.

Dürig et al. (2017) identified another de novo missense mutation in the MITF gene in an American Standardbred foal (XM_005600318.1:c.731G>A; p.Gly244Glu). This variant also affected the conserved bHLH DNA binding domain of the MITF transcription factor. The foal with this variant had an almost completely white skin and blue irsises with irregular borders.

Table S1 of Dürig et al. (2017) provides details of all MITF alleles (plus alleles at EDNRB, KIT, PAX3) known in July 2016.

Negro et al. (2017): "The g.20147039C>T intronic variant located 29.9 kb downstream from the transcription start site of the MITF gene was associated with less white markings on forelimbs (P < 0.05) in PRMe horses, with a relative contribution of 63.9%, whereas in PRE horses this variant was associated with white facial markings (P < 0.05), with a relative contribution of 63.9%."

Henkel et al. (2019) "investigated an American Paint Horse family segregating a phenotype involving white spotting and blue eyes . . . [in which] Six of eight horses with the white-spotting phenotype were deaf." Sequencing of functional candidate genes in one affected horse "revealed a heterozygous ~63-kb deletion spanning exons 6-9 of the MITF gene (chr16:21 503 211-21 566 617). We confirmed the breakpoints of the deletion by PCR and Sanger sequencing. PCR-based genotyping revealed that all eight available affected horses from the family carried the deletion."

Clinical features: Magdesian et al. 2009 demonstrated an increased risk for deafness in horses with the splashed white and/or frame overo spotting phenotype.

Horses with the SW1 allele have an increased risk for unilateral and bilateral deafness, but the exact risk is unknown. The risk for deafness and the extent of depigmentation increase, if multiple "white increasing" alleles occur simultaneously in the same horse (Hauswirth et al. 2012). The macchiato Franches-Montagnes horse carrying the p.Asn210Ser variant was deaf and had low sperm quality (Blatter et al. 2013).

Genetic testing: Genetic testing is offered by the Veterinary Genetics Laboratory of UC Davis.

Breeds: American Miniature Horse, American Paint Horse, American Standardbred, Appaloosa, Franches-Montagnes, Icelandic, Menorca, Morgan, Old-Tori, Quarter Horse, Shetland Pony, Trakehner.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
MITF microphthalmia-associated transcription factor Equus caballus 16 NC_009159.3 (21757417..21547997) MITF 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
American Paint Horse White spotting, blue eyes and deafness MITF deletion, gross (>20) 16 g.21503211-21566617del 2019 30644113
American Standardbred White MITF MITF^244Glu missense EquCab2 16 g.20094630C>T c.731G>A p.G244E 2017 27592871 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool; breed and allele information obtained from Table S1 of Durig et al. (2017) Anim Genet 48:123-124
Franches-Montagnes Macchiato MITF macchiato missense EquCab2 16 g.20103081 c.629A>G p.N210S 2012 22511888 Variant coordinates gleaned from or confirmed by Table S1 of Durig et al. (2017) Anim Genet 48:123-124
Quarter Horse Splashed white MITF SW3 deletion, small (<=20) EquCab2 16 g.20105348 c.519_523delGTGTC p.C174Sfs*20 2012 22511888 Variant coordinates gleaned from or confirmed by Table S1 of Durig et al. (2017) Anim Genet 48:123-124
American Miniature Horse American Paint Horse Appaloosa Icelandic Morgan Old-Tori Quarter Horse Shetland Pony Trakehner Splashed white MITF SW1 indel, small (<=20) EquCab2 16 g.20117302Tdelins11 2012 22511888 Variant coordinates gleaned from or confirmed by Table S1 of Durig et al. (2017) Anim Genet 48:123-124
Menorca White splashing MITF regulatory EquCab2 16 g.20147039C>T 2017 28084638

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.
2019 Henkel, J., Lafayette, C., Brooks, S.A., Martin, K., Patterson-Rosa, L., Cook, D., Jagannathan, V., Leeb, T. :
Whole-genome sequencing reveals a large deletion in the MITF gene in horses with white spotted coat colour and increased risk of deafness. Anim Genet :, 2019. Pubmed reference: 30644113. DOI: 10.1111/age.12762.
2017 Dürig, N., Jude, R., Jagannathan, V., Leeb, T. :
A novel MITF variant in a white American Standardbred foal. Anim Genet 48:123-124, 2017. Pubmed reference: 27592871. DOI: 10.1111/age.12484.
Negro, S., Imsland, F., Valera, M., Molina, A., Solé, M., Andersson, L. :
Association analysis of KIT, MITF, and PAX3 variants with white markings in Spanish horses. Anim Genet 48:349-352, 2017. Pubmed reference: 28084638. DOI: 10.1111/age.12528.
2013 Blatter, M., Haase, B., Gerber, V., Poncet, P.A., Leeb, T., Rieder, S., Henke, D., Janett, F., Burger, D. :
[Clinical evaluation of the new coat colour macchiato in a male Franches-Montagnes horse]. Schweiz Arch Tierheilkd 155:229-32, 2013. Pubmed reference: 23531944. DOI: 10.1024/0036-7281/a000451.
Haase, B., Signer-Hasler, H., Binns, M.M., Obexer-Ruff, G., Hauswirth, R., Bellone, R.R., Burger, D., Rieder, S., Wade, C.M., Leeb, T. :
Accumulating Mutations in Series of Haplotypes at the KIT and MITF Loci Are Major Determinants of White Markings in Franches-Montagnes Horses. PLoS One 8:e75071, 2013. Pubmed reference: 24098679. DOI: 10.1371/journal.pone.0075071.
2012 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., Rieder, S., Leeb, T. :
Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses. PLoS Genet 8(4):e1002653, 2012. Pubmed reference: 22511888. DOI: 10.1371/journal.pgen.1002653.
2009 Magdesian, KG., Williams, DC., Aleman, M., LeCouteur, RA., Madigan, JE. :
Evaluation of deafness in American Paint Horses by phenotype, brainstem auditory-evoked responses, and endothelin receptor B genotype. J Am Vet Med Assoc 235:1204-11, 2009. Pubmed reference: 19912043. DOI: 10.2460/javma.235.10.1204.

Edit History


  • Created by Frank Nicholas on 19 Apr 2012
  • Changed by Tosso Leeb on 23 Apr 2012
  • Changed by Frank Nicholas on 13 May 2013
  • Changed by Frank Nicholas on 12 Nov 2014
  • Changed by Frank Nicholas on 07 Sep 2016
  • Changed by Tosso Leeb on 03 Nov 2016
  • Changed by Tosso Leeb on 19 Jan 2017
  • Changed by Frank Nicholas on 01 Sep 2017
  • Changed by Frank Nicholas on 26 Mar 2018
  • Changed by Frank Nicholas on 05 Feb 2019