In other species: dog , ass (donkey) , horse , pig , llama , taurine cattle , goat , rabbit , domestic yak , alpaca , 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: 2014

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: Deaf white cat

Species-specific symbol: W

Molecular basis: David et al. (2014) reported the causal mutation of dominant white to be an insertion of a long terminal repeat (LTR) of a feline endogenous retrovirus (FERV1) of the KIT gene. David et al. (2014) identified in the same study that a full-length (7125 bp) FERV1 element insertion is associated with white spotting - see 'OMIA 001737-9685 : Coat colour, white spotting, KIT-related in Felis catus' for further detail. This causal mutation for dominant white was confirmed by Frischknecht et al. (2015).

Zhang et al. (2023) "used a pair of single-guide RNAs (sgRNAs) to delete exon 17 of KIT in somatic cells isolated from two different Chinese Li Hua feline foetuses. Edited cells were used as donor nuclei for somatic cell nuclear transfer (SCNT) to generate cloned embryos ... . The KIT D17/+ cats presented an obvious darkness reduction in the mackerel tabby coat." This study involves genetically modified organisms (GMO)

Genetic engineering: Yes - in addition to the occurrence of natural variants, variants have been created artificially, e.g. by genetic engineering or gene editing
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: As noted by Darwin in the first (1859) edition of Origin of Species, "What can be more singular than the relation between blue eyes and deafness in cats"? (page 144). In the second volume of his 1868 book entitled The Variation of Plants and Animals Under Domestication, he also mentioned the association with white coat colour: "white cats with blue eyes are almost always deaf" (page 354). This association has been much studied since then, but it is still poorly understood. Available data (summarised by Strain, 2007) suggests that the incidence of deafness amongst white cats is around 50%, comprising 40% bilateral and 10% unilateral. For cats with two, one or no blue eyes, the incidence of deafness (both bilateral and unilateral) is around 70%, 40% and 20%, respectively. And in one of the best-documented studies, Bergsma and Brown (1971) reported that around 40% of white cats have blue eyes. A segregation analysis of deafness and blue eyes by Geigy et al. (2007) suggested a gene of major effect affecting both traits, but this conclusion may be compromised by inbreeding in the population studied.

Associated gene: