In other species: dog , domestic cat , ass (donkey) , horse , pig , llama , taurine cattle , goat , rabbit , domestic yak , raccoon dog , Arctic fox

Categories: Pigmentation phene , Mortality / aging (incl. embryonic lethal)

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 172800 (trait) , 164920 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: no

Key variant known: yes

Year key variant first reported: 2019

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)

Inheritance: Valbonesi et al. (2011) provided evidence of autosomal dominant inheritance. Jones et al. (2019) concluded that their "data also support the hypothesis that the grey phenotype is autosomal dominant and that the mutation is most likely homozygous lethal."

Markers: Jackling et al. (2012) provided evidence for "a strong association but not unequivocal relationship between the BEW phenotype and KIT genotype".

Molecular basis: Jones et al. (2019) reported that their "results confirm that the classic grey phenotype in alpacas is the result of a c.376G>A (p.Gly126Arg) [omia.variant:1102] SNP in exon 3 of KIT."
Pallotti et al. (2023) "two different KIT variants segregated in white animals ...: two white alpacas ... were heterozygous (G/A) for the c.35G>A (p.Arg12His) variant, while one white alpaca ... was heterozygotes (G/C) for the c.982G>C (p.Val328Leu) variant." The authors acknowledge that these results must be validated in additional animals.
Tan et al. (2024): "One of the two KIT missense variants (XM_031688000.1:c.35G>A) [Pallotti et al., 2023] presented as a candidate causal variant for the white coat phenotype was absent from the genomes of the nine whole-genome sequenced alpacas from our study [which included completely white and white spotted animals], while the other variant (XM_031688000.1:c.982G>C) is absent in two completely white alpacas and heterozygous in two pigmented alpacas including a grey Huacaya that also carries the most likely causal missense variant (XM_031688000.1: c.391G>A) [omia.variant:1102] reported previously (Jones et al., 2019; Tan et al., 2022). Preliminary conclusions of Pallotti et al. (2023) are there-fore invalidated by our data ... ."

Clinical features: There is some evidence that the blue-eyed white (BEW) phenotype in alpacas is a variant of this locus (Jackling et al., 2012).

Prevalence: Jones et al. (2019) reported that "an additional 488 alpacas were genotyped for this [omia.variant:1102] SNP using the tetra-primer amplification refractory mutation system PCR (Tetra-primer ARMS-PCR). All classic grey alpacas were observed to be heterozygous, and 99.3% of non-grey dark base colour alpacas were found to be homozygous for the wildtype allele [G] in this position." Tan et al. (2022): "the KIT:c.376G>A [   :1102] variant was genotyped in 246 alpacas with different coat colors from Germany and Switzerland. . . . The genotype AA was not detected in any of the analyzed samples, confirming its presumed lethality . . . All animals that were phenotyped as classic grey were heterozygous (AG). . . . A completely unexpected finding was the determination of the GG genotype in one out of 10 BEW [blue-eyed white] alpacas. This BEW alpaca . . . was also reported to be deaf". As Tan et al. (2022) reported, this observation reinforces the possibility of more than one locus being involved in the BEW trait. These authors concluded by stressing the need for discovery of other likely causal variants for BEW, to "help to avoid breeding deaf alpacas".

Associated gene: