MCOA Hereditary Eye Defect in Silver Dapples

Cave painting  Source Wikipedia
Humankind seems to have always been fascinated by horse color.  As early as 25,000 years ago, prehistoric people painted spotted or dappled horses on cave walls near Pech-Merle in southern France.  Until recently, scientists believed that horses only came in black or bay colors prior to domestication; the variety of modern horse colors was created by deliberate breeding after domestication.  It was assumed that the dapple or spotted horses painted on cave walls were due to the artistic imagination, or perhaps magical beliefs, of Stone Age man.  However, recent DNA studies of the remains of prehistoric horses in Siberia and Europe have confirmed that some of these horses did have spots (Saey, 2011, p. 16).

Eye Problems and Color—An Ancient Disorder of Horses

In fact, spotted horses represented by the LP gene (a dominant gene that controls the presence of leopard-spotting in horses and is associated with the Appaloosa breed) were probably fairly common in prehistoric times.  “As for why the spotted phenotype became more rare after 14,000 years ago, the team [led by Arne Ludwig of the Leibniz Institute for Zoo and Wildlife Research in Berlin and Michael Hofreiter of the University of York in the United Kingdom] points out that some modern horse breeds with two copies of the LP gene suffer from night blindness, which would have made prehistoric horses more vulnerable to predators. The researchers speculate that the gene might have been beneficial during the Ice Age, when a white spotted coat could serve as camouflage in snowy conditions, but later became rare and disadvantageous until rediscovered by modern horse breeders” (Balter, 2011, para 6).

Goals of This Article

Leopard spotted patterning in horses is not the only color associated with genetic eye problems in horses.  The silver dapple color popular in Kentucky Mountain Horses, Rocky Mountain horses, miniature horses, Icelandics, and other breeds has been known to be associated with a genetic eye disorder Multiple Congenital Ocular Anomalies (MCOA).  Due to the concentrated breeding for this color with a limited number of foundation sires, occurrence of MCOA is as high as 50 % in the Rocky Mountain and Kentucky Mountain breeds.  The occurrence of this disorder in Icelandic horses has only recently been confirmed. 

The purpose of this article is to investigate how common are equine eye problems, outline the genetics of silver dapple color, explain what is MCOA and its relationship to the silver dapple color, discuss how the disease is inherited, explain how the desire for a rare color has created a prevalent genetic disorder in other horses breeds, and discuss how breeders and sellers can deal with this genetic defect in the Icelandic horse.

How Common Are Vision Problems in Horses

Among younger horses, vision problems are fairly uncommon.  “Ocular abnormalities are in general quite rare in horses, accounting for less than five percent of the congenital disorders reported in horses” (Andersson, Juras, Ramsey, Eason-Butler, Ewart, Cothran, and Lindgren, 2008, para 4).  Hurn and Turner (2006) conducted ophthalmic examinations of 204 thoroughbred race horses in Australia.  Horses ranged in age from 2 to 9 and consisted of both males and females.  “Potential vision-threatening eye disease was present in 15 (7.4%) different horses” (p. 97).  Like humans, older horses are more likely to develop more vision problems.   Chandler, Billson, and Mellor ( 2003) studied horses and ponies aged 15 and older and found that 67 out of 83 (80.7%) horses had ophthalmic lesions even though the owner noticed little or no impact on the horse’s vision.  A scanning of the literature on genetic vision problems in horses indicates that such problems can be influenced by color, age, sex, breed, lineage, and many other variables.

Silver Dapple—A Mutation

The silver dapple gene (Z) is responsible for a dilution effect.  It is a dominant gene—meaning only one copy of the gene needs to be present for it to have an effect.  On a black base coat, it results in a brown or chocolate color—often with dapples.  The effect on a bay coat is known as silver bay.  The silver dapple gene typically causes the long hair in the mane and tail to dilute to white and silver.  Horses with red-based coats such as chestnuts (or chestnuts affected by other dilution factors such as cremello and palomino) will not express a dilution factor; however they can carry the silver dapple gene and pass it on to their offspring.  A foal with the silver dapple color has a very pale body with a white mane and tail.  It often displays striped hooves and has white eyelashes.  These characteristics often disappear as the foal matures.  (Lord, n.d.)

And as a brief review of elementary genetics, if a horse inherits a copy of the silver dapple gene (Z) from both parents, the horse is homozygous for the color.  If the horse inherits a copy from only one parent, it is heterozygous.  Labs can now test to determine if a horse if homozygous or heterozygous for silver dapple.  Homozygous silver dapple is especially prized since all offspring except chestnut and red dilutions will have a silver dilution.

Recently scientists have localized the silver dapple color to a gene PMEL17 on horse chromosome 6.  Brunberg, Andersson, Cothran, Sandberg, Mikko,  and Lindgren (2006, para 2) found that  “DNA sequencing of PMEL17 in Silver and non-Silver horses revealed a missense mutation in exon 11 changing the second amino acid in the cytoplasmic region from arginine to cysteine (Arg618Cys). This mutation showed complete association with the Silver phenotype across multiple horse breeds.”  Translation:  The silver dapple color is caused by a mutation on the gene identified as PMEL17 on the equine chromosome 6 in which the amino acid arginine is changed to cysteine.

The silver dapple color is fairly common in the following breeds:  Icelandic, American Miniature, Kentucky Mountain, and Rocky Mountain.  The color has also been observed in the following breeds: Ardenne, Morgan, American Paint , Quarter Horse, American Saddlebred, Shetland,  and Norwegian Nordland.  The silver dapple color is found less frequently in Welsh Pony, Arabian and Swedish Warmblood breeds. 

What is MCOA?

In 1999, researchers studying Rocky Mountain horses discovered a wide variety of inherited ocular defects, which was originally described as Anterior Segment Dysgenesis (ASD) syndrome but has more recently been renamed Multiple Congenital Ocular Anomalies (MCOA).  In 2008, research by Andersson,  Juras, et al (2008) speculated that there was a linkage between MCOA and PMEL17, the gene responsible for silver dapple color, resident on equine chromosome 6q.  In 2011, Andersson, Axelsson, Dubielzig, Lindgren, and Ekesten (2011) confirmed the existence of MCOA in the Icelandic horse breed.   There is currently no genetic test for MCOA although scientists continue to work on the gene sequencing of the condition in order to develop a test.

Parts of Horse's eye--used with permission of
Dr. Trumble
Dr. N. Trumble, DVM, a veterinary ophthalmologist, wrote an excellent article entitled “Equine Anterior Segment Dysgenesis.”  Dygenesis means abnormal tissue development.  ASD, was renamed MCOA by later researchers so the author of this article is going to use MCOA for the rest of this explanation. MCOA affects the anterior or front parts of the eye--the cornea, the iris, the ciliary body (tissue behind the iris), and the lens.  The retina, which lies in the back of the eyeball, can also be affected.  Retinal abnormalities can consist of cysts, pigment streaks, retinal scarring, or even retinal detachment.  In MCOA, the above listed tissues do not develop properly-- usually during fetal development.  Generally, studies have shown that the condition is not painful and seldom compromises vision.  However advanced cases of MCOA can severely affect the vision of the horse.  Detecting signs of MCOA can be very difficult and almost always require the services of a board-certified veterinary ophthalmologist (Trumble, n.d).
The genetic inheritance of MCOA is interesting in that it is codominant.  Horses can be separated into two groups depending on the severity of eye defects they have-- the Cyst-phenotype and the MCOA-phenotype. Phenotype is defined as the physical characteristics as determined by both genetics and environment. 

“Horses referred to as having the Cyst phenotype are presumed to be heterozygous for the mutant allele [an alternative form of a gene which is located at a specific position on a specific chromosome and determines which traits can be passed on from parents to offspring] and have a minor form of ocular abnormalities compared with horses carrying two copies. The presumed heterozygous horses have cysts that originate from the temporal ciliary body, peripheral retina and/or iris. A smaller number of these horses also have moderate retinal dysplasia [abnormality of development] or retinal detachment that appears to be an extension of these cysts. The predicted homozygous horses have multiple abnormalities, primarily affecting the anterior segment of the eye. They encompass all clinical signs included in the Cyst phenotype concurrent with iris hypoplasia [incomplete development of a tissue or organ], iridocorneal angle abnormalities, miosis [constriction of the pupil], congenital cataracts, cornea globosa [rounded or protruding cornea], iridocorneal adhesions and opacification [cloudiness], nuclear cataract as well as pupils with a decreased or absent light response and that do not dilate when administered mydriatic drugs”  (Andersson, Juras, et al, 2011, para 5). 

In summary, the severity of the disease is determined by whether the horse is heterozygous or homozygous for MCOA.  If the horse is homozygous for MCOA, the ocular defects are more serious and the condition is called MCOA-phenotype.  If the horse is heterozygous for MCOA, the ocular defects are less serious and the condition is called Cyst-phenotype.

The relationship between silver dapple and MCOA is very complex and is still being researched.  The inheritance of MCOA is further complicated in that a silver dapple horse can be a carrier of the disease and exhibit no ocular problems at all; this is known as “non- penetrance of the mutation.”  In a study of Rocky Mountain horses, Ewart, Ramsey, Xu, and Meyers (2000) found that offspring of certain sires were particularly predisposed to non-penetrance—they carry both the silver dapple allele and MCOA but the visual defect does not show up in the offspring.   The researchers hypothesize the presence of a modifier gene to alter the expression of MCOA. 
MCOA Tables

Sire
Dam
Offspring
Expected Percentage
AA
AA
AA
100% unaffected
AA
AB
AA
AB
50% unaffected
50% cysts
AA
BB
AB
100% cysts
AB
AA
AA
AB
50% unaffected
50% cysts
AB
AB
AA
AB
BB
25% unaffected
50% cycsts
25% MCOA
AB
BB
AB
BB
50% cycsts
50% MCOA
BB
AA
AB
100% cysts
BB
AB
AB
BB
50% cysts
50% MCOA
BB
BB
BB
100 % MCOA
Phenotypes:   AA = unaffected,   AB = cysts,   BB = MCOA
Table 1.  Based on their study of Rocky Mountain horses, Ewart, Ramsey, et al (2000) predicted the percentage of offspring that will have MCOA-phenotype versus Cyst-phenotype when crossing horses that are heterozygous or homozygous for MCOA.  These calculated percentages do not take into account that for some horses MCOA is non-penetrative—meaning the horse carries the mutation but there is no physical effect.  

On the other hand, some sires with the silver dapple allele and MCOA produce almost exclusively offspring with MCOA-phenotypes and Cyst-phenotypes with an occasional offspring exhibiting non-penetrance.  Sometimes the sire or dam is confirmed to be a MCOA carrier only when the horse’s offspring exhibit the characteristic eye problems (Andersson, Juras, et al, 2011; Andersson, Axelsson, et al 2011).  
Certain chestnuts and red dilutions such as cremello and palomino can have the silver dapple allele and exhibit the Cyst-phenotype.  In fact since the silver dapple gene is camouflaged by the red color, a cross of two chestnuts which are heterozygous silver dapple could result in a silver dapple offspring with the more serious version of MCOA.  And some silver dapples horses may not carry the allele for MCOA or may carry the allele and pass along the condition of non-penetrance.  As the recent study by Andersson, Axelsson, et al, (2011, para 5) concludes “It is still unclear if the MCOA locus and Silver locus are two separate but closely linked loci, or if only one mutation is present with pleiotropic [having multiple effects from a single gene] effects, influencing both coat color dilution and ocular development.”
Note above figure adapted from work of Andersson, Juras, etc.

MCOA in Other Breeds

Among Rocky Mountain and Kentucky Mountain horses MCOA occur at a 50 % rate in all horses (Andersson, et al,2008;  Grahn,  Pinard,  Archer, Bellone, Forsyth, & Sandmeyer, 2008).  Visual anomalies of varying severity are associated with the silver dapple color including the colors silver black and silver bay.  As Andersson et al (2008, para 4) state, “The high incidence of ocular abnormalities in this breed is most likely due to a founder effect. Pedigree examination has revealed that a large proportion of the affected horses have a common ancestor, a stallion that is one of the few founders of the Rocky Mountain horse breed. The fact that five out of seven of the ancestral stallion's first-generation offspring had ocular abnormalities suggests that this individual did indeed carry the mutant allele.”  A similar cause is found for the presence of MCOA in Kentucky Mountain horses.  Hence breeding for the popular silver dapple or chocolate brown color has resulted in a prevalence of MCOA in these breeds. 

 Note above figure adapted from work of Andersson, Juras, etc.

“Isolated findings of MCOA syndrome have been reported in the related Kentucky Mountain Saddle Horse, Mountain Pleasure Horse and Morgan Horse breeds. Two MCOA cases have also been reported in the American Shetland pony, however this breed was developed by crossing imported Shetland ponies to finer-built domestic breeds.” (Andersson, Axelsson, et al, 2011, para 7).  Conversely, retinal cysts associated with MCOA have not been commonly reported among saddlebreds, standardbreds, Morgans, Tennessee Walkers, Welsh ponies, and Arabians (Grahn et al, 2008).  However, it may be that the incidence of MCOA among these other breeds is underreported since the expression of the disease is milder among heterozygous horses, breeders are unfamiliar with the disease, and the silver dapple gene is not readily apparent in chestnut and other red-based colors (Andersson, Juras, et al, 2008).

MCOA and Icelandics

For many years, it was thought that MCOA was caused by a recent mutation restricted to horse breeds related to the Rocky Mountain horse.  However, a new study by Andersson, Axelsson, et al (2011) has confirmed that MCOA is present in the Icelandic horse population despite these horses being genetically isolated for 1000 years.  “The Silver mutation was probably  present within the Nordic horse breeds before the colonization of Iceland during the 9th century as it is present in the Icelandic horse population on Iceland” and no known import of horses has occurred since the 10th century (Brunberg, Andersson, et al, 2006, para 9).

Andersson, Axelsson, et al (2011) studied 24 purebred, registered Icelandic horses.  Nineteen of the horses were female; 5 were males.  Ages ranged from 1 to 23, with a median age of 3.  The researchers found that 4 horses which were homozygous for silver dapple had the MCOA-phenotype, the most severe form of the MCOA syndrome; these horses did not exhibit normal light reflects.  Fourteen horses which were heterozygous for silver dapple were diagnosed with the Cyst-phenotype, the less severe form of the MCOA syndrome, and had normal light reflexes of the pupil.  Three additional horses were identified as heterozygous for silver dapple and were diagnosed as having no vision problems.  However as the researchers caution, “To date, we do not know if this was caused by limitations in our detection method or if it was due to non- penetrance of the mutation. However, horses without detectable cysts, that carry the PMEL17 mutation, still produce affected offspring” (para 27).  Used as controls, three non-silver dapple Icelandic horses were examined but displayed no signs of the Cyst- or MCOA-phenotype.

As Andersson, Axelsson, et al, (2011, para 21) conclude, “Horses with the MCOA-phenotype are at particular risk of having impaired vision, and difficulties in adapting to changing light conditions are probably a common phenomenon in these horses. Some individuals have more severe impairment of their vision, causing abnormal behavior and an inability to perform.  MCOA and PMEL17 are tightly linked, so breeding PMEL17 mutation carriers only to known non-carriers would practically eliminate the risk of producing horses with vision threatening abnormalities caused by this syndrome.”

Implications for Breeding or Buying an Icelandic Horse

Remember that MCOA has not been recognized as a common problem among Icelandics horses.  However it has been identified in the breed.  If you are thinking about buying a sliver dapple Icelandic or Icelandic with a silver dapple dilution and are concerned about visual problems in a potential purchase, discuss the topic with your veterinarian during a pre-purchase exam. “Equine MCOA is generally not detectable for the untrained eye, especially in its heterozygous state, which leaves the breeders unaware of the problem“ (Andersson, Juras, et al, 2008, para 23).  Lens opacities and other problems are frequently found during ophthalmic examinations of the horse but even experts often find it difficult to predict “the potential progression and consequences on visual function of these opacities” (McKenzie, Bryson and Marshall, 2000, p. 65). Only an equine ophthalmological specialist can help you determine the possible severity and long term consequences of any vision problem that may be discovered.   

As for breeders, N. Trumble, (n.d., pp. 2-3) DVM, University of Minnesota College of Veterinary Medicine, Department of Comparative Ophthalmology, has the following advice about MCOA (using its early term of ASD).  “The Equine Eye Registry Foundation (EERF) has created guidelines for breeders based on what is known about the mode of inheritance and the potential for ocular compromise of each condition. For example, EERF recommends that horses with cataracts are not bred, but would say it is the “breeder’s option” to breed a horse with either ciliary body cysts or retinal dysplasia…. Simply put, we are always trying to maximize the health and the quality of life of our horses. Through careful screening for ASD [MCOA] and responsible breeding, it may be possible to decrease the number of horses affected with ASD [MCOA] over time. This will in turn decrease the worry that any horse (to be bred or purchased) may be compromised by this condition.”

References
Andersson, L., Juras, R., Ramsey, D., Eason-Butler, J., Ewart, S., Cothran, G., and Lindgren, G.  (2008).  Equine Multiple Congenital Ocular Anomalies maps to a 4.9 megabase interval on horse chromosome 6. BMC Genetics, 9:88.  Last found April 5, 2012 at http://www.biomedcentral.com/1471-2156/9/88
Andersson, L., Axelsson, J., Dubielzig, R., Lindgren, G. and Ekesten, B.  (2011).  Multiple congenital ocular anomalies in Icelandic horses.  BMC Veterinary Research, 7:21.  Last found February 2, 2012 at http://www.biomedcentral.com/1746-6148/7/21
Balter, M.  (November 7, 2011).  Cave paintings showed true colors of stone age horses.  Science Now.  Last found on April 1, 2012 at http://www.wired.com/wiredscience/2011/11/cave-painting-colors/
Brunberg, E., Andersson, L., Cothran,G.,  Sandberg, K, Mikko, S., and Lindgren, G. (2006).  A missense mutation in PMEL17 is associated with the Silver coat color in the horse.  BMC Genet. 2006; 7: 46.  Most recently found January 5, 2012 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1617113/?tool=pubmed
Ewart, S., Ramsey, D, Xu, J., Meyers, D.  (2000).  The horse homolog of congenital aniridia conforms to codominant inheritance.  The Journal of Heredity, 91 (2): 93-98.
Grahn,B.,  Pinard, C., Archer, S. , Bellone. R., Forsyth, G., & Sandmeyer, L.  (2008). Congenital ocular anomalies in purebred and crossbred Rocky and Kentucky Mountain horses in Canada.  The Canadian Veterinary Journal, 49(7): 675–681  Last found April 3, 2012 at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430397/
Hern, S., & Turner, A.  (2006). Ophthalmic examination findings of Thoroughbred racehorses in Australia, Veterinary Ophthalmology (2006) , Volume: 9, Issue: 2, Publisher: null, Pages: 95-100
Lord, J.  (n.d.)  The silver (AKA silver dapple) dene.  Most recently found on April 1, 2012 at http://www.horsecolor.com/dilutions/silver_dapple.htm
McKenzie, Bryson and Marshall.  Lens opacities in the horse: a clinical classification. Vet Ophthalmology 2000;3(2-3):65-71
Saey, T.  (December 17, 2011).   Ancient horses spotted.  Science News, p. 16.
Trumble, N.  (n.d.) Equine Anterior Segment Dysgenesis.  Last found April 1, 2012, at www.cvm.umn.edu/umec/prod/groups/cvm/@pub/@cvm/@equine/documents/asset/cvm_asset_121874.pdf


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