In other species: rabbit , pig , cattle , dog , domestic cat , llama , alpaca , Arctic fox , ass , raccoon dog , domestic yak , goat

Categories: Pigmentation phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 172800 (trait) , 164920 (gene)

Links to MONDO diseases: No links.

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Considered a defect: no

Key variant known: yes

Year key variant first reported: 2005

Cross-species summary: The dominant white gene is one of a number of genes that regulate normal growth and proliferation of cells. In fact, it encodes a protein that protrudes through the cell membrane, relaying 'messages' across the membrane, from outside to inside the cell. The transmembrane domain of the protein is a receptor for a growth factor (a protein produced by one type of cell, that acts on another type of cell). The domain inside the cell has tyrosine kinase activity. When a growth factor binds to the receptor on the outside of the cell, this stimulates tyrosine kinase activity inside the cell, which sets off a cascade of phosphorylations, resulting in activation of transcription factors, which in turn activate genes, resulting in multiplication of stem cells, including melanocyte precursor cells, in the developing embryo. This whole process is known as a signal transduction pathway. During embryonic development, the melanosome precursor cells migrate from the neural crest down either side of the body. Under normal circumstances, they eventually meet at the centre of the belly. The cells then proliferate in all directions until they meeting neighbouring cells, thereby filling up all available areas, resulting in a solid mass of melanocytes over the entire body. The dominant white allele produces a defective transmembrane protein which is unable to relay 'messages', resulting in a lack of melanocytes, and hence white coat colour. An interesting aspect of the dominant white gene is that if it is activated at the wrong time, the result can be excess and uncontrolled proliferation of stem cells; in other words, cancer. In fact, at some time in the past, a feline retrovirus (the Hardy-Zuckerman 4 feline sarcoma virus) 'picked up' (by transduction) a copy of the dominant white gene from a cat, and incorporated this gene into its own genome. When this retrovirus infects cats, it activates its own copy of the gene at inappropriate times, causing sarcoma - a malignant tumour of cells derived from connective tissue. Retroviral genes that cause cancer are called oncogenes. The original host version of an oncogene is called a proto-oncogene. Thus, the dominant white gene is actually a proto-oncogene. In this particular case, the oncogene was discovered and named v-kit (where 'v' indicates a viral version of the gene) long before its association with white coat colour was established. The corresponding proto-oncogene is called c-kit, where 'c' stands for cellular. After the discovery and cloning of v-kit in the feline retrovirus by Besmer et al. (1986; Nature 320:415-421), c-kit was identified and mapped first in humans, by Mattei et al. (1987; Cytogenetics and Cell Genetics 46:657 only), and then in mice (Chabot et al., 1988; Nature 335:88-89, 1988), where it was shown to be identical with the long-recognised white-spotting (W) locus. Three years later, Giebel and Spritz (1991; Proceedings of the National Academy of Sciences 88:8696-8699) showed that mutations at the c-kit gene in humans cause piebaldism, which is the human homologue of white spotting (see the MIM entry at the top of this page)

Species-specific name: Tobiano, Sabino

Mapping: Mau et al. (2004) mapped this trait to a region of chromosome ECA3 containing the KIT gene.

Markers: From a study of 1054 American Paint horses registered with the American Paint Horse Association (APHA), Brooks et al. (2020 reported that "The W20 allele within the KIT gene, independent of other known spotting alleles, was strongly associated with the APHA-defined white-spotting phenotype (P = 1.86 × 10-18 ), refuting reports that W20 acts only as a modifier of other underlying white-spotting patterns."

Molecular basis: Using the comparative candidate-gene strategy (based on the KIT gene being associated with similar coat-colour-phenotypes in humans and pigs), Brooks and Bailey (2005) sequenced the KIT gene in horses of each of the three genotypes at a Sabino-spotting locus they called Sabino 1, and identified a splice variant, namely "a base substitution for T with A in intron 16, 1037 bases following exon 16" that results in the skipping of exon 17 and which was entirely associated with the SB1 allele. Homozygosity for this allele "results in a complete or nearly completely white phenotype". Haase et al. (2007) showed that the dominant white coat colour is due to a range of mutations in the KIT gene across a range of breeds. Brooks et al. (2007) showed that the tobiano pattern is due to a large paracentric inversion that begins just downstream of the KIT gene. In the words of Brooks et al. (2007), the "inversion may disrupt regulatory sequences for the KIT gene and cause the white spotting pattern". Haase et al. (2008) showed that the same inversion is the cause of this coat colour in a range of German horse breeds, indicating that it is an old mutation. Additional KIT mutations associated with white or white spotting have been reported by Haase et al. (2009), Holl et al. (2010), Haase et al. (2011) and Hauswirth et al. (2013). To help keep track of the large number of apparently functional mutations, Haase et al. (2009) proposed a KIT-allele naming system (W1, . . . , W11) for the 11 mutants then recognised. The new allele reported by Holl et al. (2010) is W12. Haase et al. (2011) reported new alleles W13-W17. The three new alleles reported by Hauswirth et al. (2013) are named W18, W19, and W20. Another new allele, W21, was reported by Haase et al. (2015). W22 was reported by Dürig et al. (2017) and W23 by Holl et al. (2017), who also provided the first report of a viable W15 homozygote, which was completely white, the first such reported case of viable homozygosity for any W allele.

Negro et al. (2017): "a missense mutation (p.Arg682His) in KIT [= allele W20] was associated with white facial markings (P < 0.05) and with total white markings (P < 0.05) in PRMe horses. The relative contribution of this variant to white markings in PRMe horses was estimated at 47.6% (head) and 43.4% (total score). In PRE horses, this variant was also associated with hindlimb scores (P < 0.05) with a relative contribution of 41.2%."

Capomaccio et al. (2017) reported a de novo likely causal (splicing) variant (NC_009146.2:g.77736559C>T, called allele W24) in a white Italian Trotter born to two non-white (bay) parents.

Hoban et al. (2018) reported three new likely causal variants, which they designated "W25 (p.Leu223Pro) [in a Thoroughbred family], W26 (p.Ser846Valfs*15) [in the same Thoroughbred family] and W27 (p.Cys491Trp) [in a second Thoroughbred family]". These authors also identified variant W13 in a Miniature Horse family.

Hug et al. (2019) reported a "1273‐bp deletion spanning parts of intron 2 and exon 3 of the equine KIT gene" as the likely causal variant for "a German Riding Pony with white‐spotting coat colour phenotype" very similar to that attributed to allele W22 (see above). The authors designated this newly-reported variant as W28.

Table S1 of Hug et al. (2019) provides details of all KIT alleles (plus alleles at PAX3, MITF and EDNRB) known in June 2019.

Martin et al. (2020) reported that "extensive coat white patterning in a family of Berber horses" is due to "a single missense mutation (g.79548244, c.2020T>A; p.L674H) at the site of the second W17 variant. We propose to designate this variant as W30."

Patterson Rosa et al. (2021) “performed a candidate-gene exon sequencing approach on KIT and MITF … within 2 families of horses of unknown white spotting. Family 1 (Fam1, N = 5) consisted of a Quarter Horse stallion and 4 offspring with white spotting pattern ranging from legs, lower ventral, and head regions with jagged borders, to almost complete white. The second family (Fam2, N = 7) consisted of 6 half-sibling American Paint Horse/Quarter Horse and their dam, demonstrating unpigmented limbs with belly spots and an extensive white patterning on the face. … This approach resulted in 2 variants significantly associated with familial phenotypes, where Fam1 variant is an indel leading to a frameshift mutation [= allele W31], and Fam2 a non-synonymous SNP [= allele W32]. … W32, may have a subtle impact on receptor function or could be in linkage with a non-coding or regulatory change creating the mild spotting pattern observed in this family.”

Esdaile et al. (2021): "Screening 19 unregistered all-white Shetland ponies for 16 white patterning markers identified 14 individuals whose phenotype could not be explained by testing results. In evaluating other known dominant white variants, 14 horses were heterozygous for W13. ... Genotyping known white spotting variants in 30 owner-reported white animals (25 Miniature Horses and five Shetland ponies) identified two additional W13/N American Miniature Horses. No homozygous W13 individuals were identified and W13/N ponies had a similar all-white coat with pink skin phenotype, regardless of the other white spotting variants present, demonstrating that W13 results in a Mendelian inherited dominant white phenotype and homozygosity is likely lethal."

Esdaile et al. (2022) reported "KIT:c.2783A>T as a causal de novo variant for the sabino-like pattern of a Standardbred", naming this variant as W33.

Patterson Rosa et al. (2022) reported "a missense variant in KIT (rs1140732842, NC_009146.3:g.79566881T>C, p.T391A)" with a significant association with Average Grade of White, calculated as the mean of subjective assessments of three observers on photographs of 147 horses. The authors named this variant W34. They also reported that W34 (in exon 7) is in strong linkage disequilibrium with W19 (in exon 8; 13.1kb from W34), and interacts with the MC1R locus.

Prevalence: Druml et al. (2018) reported that the SB1 variant is "present in three breeds (Haflinger, 14 out of 98; Noriker, four out of 189; Lipizzan one out of 329) . . . None of the SB1/sb1-carrier horses met the criteria defining the Sabino1 pattern according to current applied protocols."

Esdaile et al. (2021): "The estimated allele frequency of W13 in the American Miniature Horse was 0.0063 (79 N/N, 1 W13/N) and the allele was not detected in a random sample (n = 59) of Shetland ponies." In the same study 14 out of 19 all-white unregistered Shetland ponies were heterozygous for the W13 variant.

Breeds: American Paint (Horse) (VBO_0000897), Appaloosa (Horse) (VBO_0000904), Arab (Horse) (VBO_0000905), Berber, Germany (Horse) (VBO_0010413), Camarillo White Horse, United States of America (Horse) (VBO_0016869), CH-Warmblut, Switzerland (Horse) (VBO_0011249), Freiberger (Horse) (VBO_0000965), German Riding Pony (Horse) (VBO_0000972), Haflinger (Horse) (VBO_0000978), Holsteiner (Horse) (VBO_0000986), Iceland Pony (Horse) (VBO_0000990), Japanese Draft, Japan (Horse) (VBO_0016870), Lipizzan horse (Horse) (VBO_0001014), Miniature Horse (Horse) (VBO_0016848), Noric (Horse) (VBO_0001030), Oldenburg (Horse) (VBO_0001034), Quarter Horse (Horse) (VBO_0001057), Shetland Pony (Horse) (VBO_0001066), Süddeutsches Kaltblut, Germany (Horse) (VBO_0011384), Thoroughbred (Horse) (VBO_0001083), Tori hobune, Estonia (Horse) (VBO_0011097), Traditional Gypsy Cob, United Kingdom of Great Britain and Northern Ireland (Horse) (VBO_0011496), Trottatore Italiano, Italy (Horse) (VBO_0011598), Welsh Pony (Horse) (VBO_0001091).

Associated gene: