OMIA 000214-9796 : Coat colour, white spotting in Equus caballus
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|
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 fromÂ 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|
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., 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 50:172-174, 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.|
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