White patterns in horses are known to cause bright blue eyes. The white pattern most often associated with blue eyes in horses is the splashed white pattern. KIT gene mutations (including Dominant White, Sabino, and Tobiano) are not as frequency associated with blue eyes but why? The reason lies with gene function and the distribution of pigment during embryonic development.
Pigmentation in the iris of the eye, skin, and hair begin at the neural crest and are distributed throughout the body during embryonic development 1. When this process is disrupted, usually by mutations that alter gene function, white patterns can result. However, here lies a mystery. KIT gene mutations are not often associated with blue eyes even though the rest of the animal is entirely white. Why should there be an anomaly, such as this, in the pigment distribution? The answer is that not all the pigmentation in the eye is derived from the neural crest. Pigmentation of the retinal pigment epithelium, a thin layer of heavily pigmented cells in retina of the eye (hereafter referred to as RPE), are not derived from the neural crest, but rather the optic neuroepithelium2. Because of the separate origin of these two areas of the eye they are affected by different genes. MITF gene (where the SW1 and SW3 mutations are located) affects both neural crest derived pigment and the optic neuroepithelium pigmentation1, as does PAX3 where Splashed White 2 is located. This can result in eyes that are blue due to lack of pigment in both the iris and the retina including the RPE3. Images of human patients with Waardenburg syndrome type 2 show a phenotype remarkably similar to horses with splashed white. Both can be affected with sapphire blue eyes and heterochromia irides (eyes of different colors or the same eye with different colors) and both of these phenotypes are the result of MITF gene mutations. 3
This girls blue eyes are most likely caused by Waardenburg Syndrome type 2. Note the bit of white forelock and eye brow.
However, in comparison to the MITF gene the KIT gene is not thought to affect melanocytes that originate from the optic neuroepithelium 42 This leaves the RPE within the eye pigmented even if the iris is devoid of pigment. “Hence, pigmentation of the RPE and the back layer of the iris is sufficient for the visual appearance of a black eye.”2This explains the “black eyed white” phenotype in many species including horses.
So what does this mean? If scientists are correct, it means that KIT gene mutations alone (ie Tobiano, SB1, classic roan and all the W mutations) are incapable of causing blue eyes. Because the KIT gene is not responsible for the development of a pigmented RPE, an animal completely devoid of pigmentation in the skin, hair, and iris due to a KIT gene mutation, can still have a pigmented RPE which is sufficient to cause the appearance of a black eye. 2
An illustration of the eye showing the upper front quarter. I have highlighted the marker for the RPE to make it easier to find.
So, why do horses with KIT gene mutations sometimes have blue eyes? The answer is simple, they have a secondary mutation in a gene that can affect the pigmentation of the entire eye not just the iris. It is known that mutations in genes such as MIFT and KIT can produce a “boost” effect when they are both present in a single animal. This is because the function of these genes overlap to some extent. 5 This type of boost effect is most commonly seen in tobiano horses who also have the SW1 (splashed white type 1) mutation. Given that there are perhaps dozens of white patterns that cause “normal” leg and face white yet to be located, it is possible that a mutation yet to be discovered is responsible for these anomalous blue eyes.
It should be noted that some researchers also feel that mutations in EDNRB (where the Frame/LWO mutation is located) cannot cause blue eyes for the same reasons discussed above for KIT gene mutations.42 However, this is at odds with Lethal White foals who have blue eyes and also a similar mutation found in sheep that results in lambs with blue eyes who die shortly after birth. 6 It may be that in order for mutations in this gene to cause blue eyes the effects of the mutations must be so extensive as to be lethal. However, I was unable to find any research to support or refute this hypothesis.
- 1. a. b. Hozumi, H. et al. Impaired development of melanoblasts in the black-eyed white Mitf(mi-bw) mouse, a model for auditory-pigmentary disorders. Genes Cells 17, 494–508 (2012).
- 2. a. b. c. d. e. Bharti, K., Nguyen, M.-T. T., Skuntz, S., Bertuzzi, S. & Arnheiter, H. The other pigment cell: specification and development of the pigmented epithelium of the vertebrate eye. Pigment Cell Res. 19, 380–94 (2006).
- 3. a. b. Ohno, N. et al. Clinical findings in Japanese patients with Waardenburg syndrome type 2. Jpn. J. Ophthalmol. 47, 77–84
- 4. a. b. Lamoreux, M. Lynn. The Colors of Mice: A Model Genetic Network. Chichester, West Sussex: Wiley-Blackwell, 2010. Print. p.130-131
- 5. Hou, L., Panthier, J. J. & Arnheiter, H. Signaling and transcriptional regulation in the neural crest-derived melanocyte lineage: interactions between KIT and MITF. Development 127, 5379–89 (2000).
- 6. Lühken, G., Fleck, K., Pauciullo, A., Huisinga, M., & Erhardt, G. (2012). Familiar hypopigmentation syndrome in sheep associated with homozygous deletion of the entire endothelin type-B receptor gene. PloS one, 7(12), e53020. doi:10.1371/journal.pone.0053020