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

Possibly relevant human trait(s) and/or gene(s) (MIM number): 172800

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Dominant

Considered a defect: no

Key variant known: yes

Year key variant first reported: 1996

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: The dominant autosomal inheritance of white coats in pigs was determined soon after the re-discovery of Mendelism, by Spillman (1906). The results of Rubin et al. (2012) indicate four alleles at this locus, namely normal colour (recessive i), Dominant white (I; this entry), Patch (I^p; OMIA 001743-9825) and Belt (OMIA 001745-9825). (with thanks to Leif Andersson)

Mapping: In 1992, Johansson et al. showed that the porcine dominant white locus (designated I) is located on pig chromosome SSC8, in a region homologous with the region of mouse chromosome 5 that contains three white-spotting genes, including the c-kit proto-oncogene, which is the gene for dominant white spotting (W) in the mouse. This gene encodes the mast/stem cell growth factor receptor (MGFR). This result of Johansson et al. (1992) immediately suggested KIT as a very likely comparative positional candidate gene for dominant white spotting in pigs.

Molecular basis: In another excellent example of the power of comparative mapping (similar to the case of malignant hyperthermia in pigs), Johansson Moller et al. (1996) investigated the porcine KIT gene as a comparative positional candidate gene for dominant white spotting (based on the mapping results of Johansson et al. (1992) described above). Johansson Moller et al. (1996) were able to show that KIT is, indeed, the gene for dominant white in pigs: the white allele contains a duplication of part or all of the KIT gene, and this duplication results in a lack of melanocytes in the skin. In 1998, Marklund et al reported the molecular details of variants at this locus: the fully dominant white allele results from a splice mutation (a substitution of A for G in the first nucleotide of intron 17, resulting in the loss of exon 17), which is presumed to give rise to a MGFR with impaired or absent tyrosine kinase activity. Another white allele, which is only partially dominant, results from a duplication of the KIT gene, which presumably affects gene expression.

Following analysis of whole-genome resequencing data from tens of pigs from a wide range of breeds, Rubin et al. (2012) have enhanced our understanding of this intriguing locus: the Dominant white allele (I) carries at least three causal polymorphisms, namely a 450 kb duplication (also present in Patch - see OMIA 001743-9825), the splice mutation mentioned above (unique to Dominant white) and smaller duplication(s) (that occur within the 450kb duplication) causing Belt (see OMIA 001745-9825).(with thanks to Leif Andersson)

Genetic testing: Li et al. (2018) reported "a simple, rapid method, with high specificity and stability, for the detection of the KIT genotype in pigs was established using TaqMan MGB probe real-time quantitative PCR."

Associated gene: