Age-dependent Gene Expression: The Grey Locus in Horses

True albino--the inability to manufacture melanin--has never been documented in horses.

Several different genes with alternate alleles can produce a white horse.

• white allele(s) of the KIT gene
• graying allele of the syntaxin 17 gene (STX17), known as the "Gray Gene"
• recessive allele of the sabino-1 gene (LWO)
• lethal recessive allele of the frame overo gene (sb1)
• homozygous dilution alleles producing perlino or cremello coat
• Appaloosa and Paint horses can be almost pure white due to low expressivity of their pigmentation genes.

Among these, only the Graying allele exhibits age-dependent expression.

Gray Gene Horses born with the graying allele of the KIT gene can be born any color. As they age, the hair follicles progressively lose the ability to manufacture melanin. The coat takes on a "dappled" pattern that gradually becomes completely white. Heterozygotes tend to retain some pigmentation. Homozygotes usually progress to completely white. The skin does not change color, and continues to produce melanin. The Graying Gene and Melanoma The Graying gene has been linked with an unusually high risk of dermal melanoma. More than 70% of dapple grey horses over the age of 15 years develop melanomas. Homozygotes are at greater risk than heterozygotes. Gray horses also homozygous recessive (aa) at the Agouti locus (uniformly pigmented, not bay) are at even higher risk. The graying trait in horses has been identified as a 4.6 kb duplication in intron 6 of the syntaxin 17 (stx17) gene.(1) Syntaxin proteins mediate intracellular vesicle fusion. Certain human cancers (often of the liver) are also associated with syntaxin localization errors. The mechanism of syntaxin mutations leading to increased risk of cancer is not yet known. The graying gene in horses may provide a useful model.

True White Horses True white horses are rare, and are not albino. They are born white with pink skin, and remain white all of their lives. The white coat and skin are due to a lack melanin deposition in the skin and hair. The eyes are pigmented (blue or brown). True white has been traced to a dominant loss-of-function in the KIT gene, which encodes one of many receptor tyrosine kinases (RTKs), which serve as receptors for hormones, cytokines, and growth factors. The exact mechanism of the mutations effect on depigmentation is not fully understood.

References:

(1) Pielberg G.R., Golovko A., Sundstrom E. et al. 2008. A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse. Nature Genetics, 40 (8):1004-1009.

(2) Hintz, H. F. and VanVleck, L. D. 1979. Lethal Dominant Roan in Horses. Journal of Heredity, 70:145-146