Disease and Coat Color

Most of us are aware that some diseases can be inherited.  These inheritable diseases are the result of mutations, affecting the functioning of a gene, thus causing illness.  Examples of inheritable diseases in humans include Sickle Cell Anemia and Cystic Fibrosis.  Something that is not commonly realized however, is is that the same mutations that cause variations in color, also affect the function of genes.  The alteration of coat color is in fact the caused by the change in function of the gene.  Because these color altering mutations affect gene function, some of the same mutations that cause altered coat color can cause disease.  It is therefore necessary for breeders to educate themselves about genes that alter both color and cause disease in order to breed responsibly.  

A Lethal White Foal the result of a breeding between a Frame Positive Mare and a Stallion the Owner said was Negative.

Silver in horses: Silver in horses is caused by a dominant mutation in SILV (aka PMEL17).  In most cases, horses who are heterozygous for Silver are nonsymptomatic but many have ciliary cysts.  These cysts should not affect vision and are invisible without special veterinary equipment.  Horses who are homozygous for silver may have more severe eye problems.  Silver can cause Cornea globosa, severe iridal hypoplasia, uveal cysts, cataracts, and retinal detachment.  Chestnut horses that carry silver have the same risk for eye problems.1

Merle in dogs: Merle in dogs is the result of a mutation in SILV and, like silver in horses, can result in eye abnormalities.  However, Merle in dogs can cause other abnormalities as well.  Mere is an incomplete dominant that causes minimal health problems when heterozygous.  These can include mild to severe deafness and near sightedness (auditory dysfunction, increased intraocular pressure and ametropic eyes).  However, when homozygous severe disabilities can result.  These include multiple abnormalities of the skeletal, cardiac, and reproductive systems.2

Dominant White in horses:  Most but not all Dominant white mutations in horses are lethal in utero when Homozygous.  This means that early in gestation the embryo will become non-viable and be reabsorbed by the mare.  The Dominant Whites in horses are caused by KIT gene mutations.  There are currently 20 Dominant White Mutations designated W1-W20.  Most likely more DW mutations will be found in the future.  

Splashed White 2 (SW2) in horses:    Due to studies of similar mutations in other species SW2 in horses is thought to be embryonic lethal when homozygous.  SW2 is the result of a mutation in PAX3.3

Splashed White in horses (all Splash Variants):  All Splashed white variants have a chance to cause deafness.  Not all splashed white horses are deaf however.  It is thought to be caused by lack of pigment in the inner ear and affects horses with more white towards the ears. So, why are Dominant White and Frame mutations that affect large areas of the head not known to cause deafness?  The reason has not yet been determined.  Splashed white is caused by mutations in MITF and PAX3.3

Leopard Complex (LP) in horses:  Leopard Complex in horses is closely associated with  Congenital Stationary Night Blindness.  Meaning the horses have difficulty seeing at night.  The causative mutation is thought to be the same as the mutation for LP.    The conditions occurs in horses that are homozygous for Leopard Complex (LP) but in most cases does not seriously impede function.  Both LP and Congenital Stationary Nightblindness have been mapped to TRPM1.4

Harlequin in Dogs (specifically Great Danes):  Harlequin is what is known as a compound pattern.  This means that two separate genes are needed for Harlequin to express.  The first is Merle and the second is Harlequin itself.  Without Merle, Harlequin will not express but when Merle is present it alters the merle pattern to leave large blotches of color on a white background.  Although the prefered base color is black Harlequins can be any color found in Great Danes.  Harlequin is embryonic Lethal when homozygous.5

Roan in Cattle:  A semi-dominant mutation which results in an almost white individual when homozygous.  Some homozygous females suffer from reproductive tract abnormalities including missing or incomplete vaginas, uteri, and uterine horns.  This is also known as “White Heifer Disease”.  Roan is the result of a KIT gene mutation.6,7

Frame (LWO) horses:  Frame in horses is the result of a mutation in the EDNRB gene.   It is lethal when homozygous but unlike some other white spotting patterns that are embryonic lethal, foals that are homozygous for frame are born alive but with an incomplete digestive tract.  Such a foal will be white or nearly white and will die within 72 hrs unless humanely euthanized.8

Lavender foal syndrome horses (specifically Arabians):   Lavender foal Syndrome is not a color dilution per se but it does affect color with foals being born a color close to lavender hence the name.  Foals display a variety of neurologic impairment including tetanic-like seizures, opisthotonus, stiff or paddling leg movements and nystagmus.  These abnormalities prevent the foal from standing and nursing.  There is no treatment.  Foals die soon after birth or are euthanized.  Lavender foal syndrome is the result of a mutation in MYO5A.9  

Piebald Spotting in dogs:  Piebald spotting in dogs at times results in deafness, much like Splashed White in horses.  Piebald spotting is also the result of a MITF gene mutation.10

Dilution in dogs:  Skin problems...Although some claim that the skin problems in Blue dogs are the result of a closely linked mutation, evidence seems to point to it mutation that causes the blue dilution being the causative mutation for the skin problems as well.  The evidence for this is the way the skin ailment functions.   Causing clumps of pigment in the hair shaft that fracture as the hair emerges from the skin.   Since MLPH, the gene responsible for Dilution, is responsible for pigment transport and clumping pigment is the cause of the dilute color, it is logical that the causative mutations are the same.  At least in the breeds studied.11  

Ashen in mice:  In addition to a dilute coat color, ashen mice also have platelet defects which result in an increase in the time necessary for wounds to clot. Ashen in mice is the result of a mutation in Rab27a.12

Dominant White and Piebald spotting in cats:  Like Splashed White in horses and Piebald in Dogs, Dominant White and Piebald in cats both have a chance to cause deafness.  It seems to affect blue eyed cats more than cats with other colors or odd colored eyes.  It is not known what gene mutation is responsible for these white patterns in cats.  

Gray in horses:  Gray in horses is caused by a mutation in STX17 (syntaxin-17).  It causes progressive loss of pigment from the hair shaft and in some cases from the skin as well.  It is directly linked to melanomas most of which are benign.  After the age of 15 as high as 80% of gray horses will have these tumors.  While in most cases these tumors are not lethal, they can lead to death if they grow large enough to impede organ function.13  

1)Ségard, E. M., Depecker, M. C., Lang, J., Gemperli, A. and Cadoré, J.-L. (2013), Ultrasonographic features of PMEL17 (Silver) mutant gene–associated multiple congenital ocular anomalies (MCOA) in Comtois and Rocky Mountain horses. Veterinary Ophthalmology. doi: 10.1111/vop.12021

2)Clark LA, Wahl JM,Rees CA, Murphy KE, Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc Natl Acad Sci U S A2006;103:1376-1381. Abstract/FREE Full Text

3) Hauswirth, R., Jude, R., Haase, B., Bellone, R. R., Archer, S., Holl, H., Brooks, S. a, et al. (2013). Novel variants in the KIT and PAX3 genes in horses with white-spotted coat colour phenotypes. Animal genetics, 1–3. doi:10.1111/age.12057

4) Bellone, R. R., Forsyth, G., Leeb, T., Archer, S., Sigurdsson, S., Imsland, F., Mauceli, E., et al. (2010). Fine-mapping and mutation analysis of TRPM1: a candidate gene for leopard complex (LP) spotting and congenital stationary night blindness in horses. Briefings in functional genomics, 9(3), 193–207. doi:10.1093/bfgp/elq002

5) Clark, L. A., Tsai, K. L., Starr, A. N., Nowend, K. L., & Murphy, K. E. (2011). A missense mutation in the 20S proteasome β2 subunit of Great Danes having harlequin coat patterning. Genomics, 97(4), 244–8. doi:10.1016/j.ygeno.2011.01.003

6) Charlier, C., Denys, B., Belanche, J. I., Coppieters, W., Grobet, L., Mni, M., Womack, J., et al. (1996). Microsatellite mapping of the bovine roan locus: A major determinant of White Heifer Disease. Mammalian Genome, 7(2), 138–142. doi:10.1007/s003359900034

7) Seitz, J. J., Schmutz, S. M., Thue, T. D., & Buchanan, F. C. (1999). A missense mutation in the bovine MGF gene is associated with the roan phenotype in Belgian Blue and Shorthorn cattle. Mammalian Genome, 10(7), 710–712. doi:10.1007/s003359901076

8) Metallinos, D. L., Bowling, a T., & Rine, J. (1998). A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung disease. Mammalian genome : official journal of the International Mammalian Genome Society, 9(6), 426–31. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9585428

9) Brooks, S. a, Gabreski, N., Miller, D., Brisbin, A., Brown, H. E., Streeter, C., Mezey, J., et al. (2010). Whole-genome SNP association in the horse: identification of a deletion in myosin Va responsible for Lavender Foal Syndrome. PLoS genetics, 6(4), e1000909. doi:10.1371/journal.pgen.1000909

10) Schmutz, S. M., Berryere, T. G., & Dreger, D. L. (2009). MITF and White Spotting in Dogs: A Population Study. Journal of Heredity, 100(Supplement 1), S66–S74. doi:10.1093/jhered/esp029

11) Philipp, U., Hamann, H., Mecklenburg, L., Nishino, S., Mignot, E., Günzel-Apel, A.-R., Schmutz, S. M., et al. (2005). Polymorphisms within the canine MLPH gene are associated with dilute coat color in dogs. BMC genetics, 6, 34. doi:10.1186/1471-2156-6-34

12) Wilson, S. M., Yip, R., Swing, D. a, O’Sullivan, T. N., Zhang, Y., Novak, E. K., Swank, R. T., et al. (2000). A mutation in Rab27a causes the vesicle transport defects observed in ashen mice. Proceedings of the National Academy of Sciences of the United States of America, 97(14), 7933–8. doi:10.1073/pnas.140212797

13) http://www.cvm.umn.edu/equinegenetics/ghmelanoma/home.html