Gene or region: MITF or PAX3
Reference allele: many, see below
Mutant allele: many, see below
Affected Breeds: many, see below
High confidence, mutations in MITF and PAX3 have been well-documented to cause
white spotting in both the horse and other species, even humans!
Splashed white overo is a white spotting pattern characterized by extended white markings on the legs, face, and often tail/belly, sometimes described as a horse that was dipped in paint. Splashed white horses often have blue or partially blue eyes, and can be deaf (dependent upon the variant and the placement). Splashed white 1 (SW1) is inherited as an incomplete dominant trait, whereas the other six known splashed whites (SW2, SW3, SW4, SW5, SW6, SW7) are completely dominant. This signifies that horses that are heterozygous for splashed white 1 (SW1/N) will have less white than horses that are homozygous (SW1/SW1). Many SW1/N horses have fairly low/”normal” markings, often with blue or partially blue eyes. On the other hand, horses heterozygous for the other variants (SW2/N, SW3/N, SW4/N, SW5/N, SW6/N, SW7/N) generally display the typical splashed white pattern. Homozygous horses for SW2 are rare, and none have been identified for SW3 through SW7.
Because splashed white variants are found in two separate genes, horses can have more than two splashed white alleles. Except in rare cases, horses can have one or two copies of SW1 or SW3, and one or two copies of SW2 or SW4. The original splashed white paper noted that horses with both SW1 and SW2 had larger white markings than horses with only SW1 or SW2. One horse was homozygous for SW1 and heterozygous for SW2 (variants of different genes, thus genotype SW1/SW1 SW2/N) and was born completely white and deaf. They also observed one horse with both SW1 and SW3 (both variants of MITF, thus genotype SW1/SW3) that was completely white as well.
*Discovered at Etalon!
MITF is a transcription factor that serves to activate several key genes involved in the development of pigmentation. Mutations in both the horse and in other species have led to white spotting, deafness, and sterility. The SW1 mutation is a short insertion within the promoter region of MITF that likely interferes with normal gene regulation. The SW3 mutation is a short deletion within MITF that leads to a premature stop codon and thus a severely truncated protein.
PAX3 is a transcription factor that is vital for normal development. Mutations in other species have led to white spotting, deafness, and alveolar rhabdomyosarcoma. In the horse, only deafness and white spotting have been reported. Both the SW2 and SW3 mutations result in an amino acid substitution which likely alters the DNA binding ability and thus function of the encoded protein.
Patterson, et. al., "Non-frameshift deletion on MITF is associated with a novel splashed white spotting pattern in horses (Equus caballus)" (2022) Anim Genet. 2022 Jun 7. doi: 10.1111/age.13225
Henkel, et al., "Whole-genome sequencing reveals a large deletion in the MITF gene in horses with white spotted coat colour and increased risk of deafness" (2019) Anim Genet. 50: 172-4.
Hauswirth R et al., “Mutations in MITF and PAX3 cause "splashed white" and other white spotting phenotypes in horses.” (2012) PLoS Genet. 8: e1002653.
Hauswirth R et al., “Novel variants in the KIT and PAX3 genes in horses with white-spotted coat colour phenotypes.” (2013) Anim Genet. 44: 763-5.
Magdesian, KG et al., "A de novo MITF deletion explains a novel splashed white phenotype in an American Paint Horse." (2020) The American Genetic Association