The Horse Homolog of Congenital Aniridia
Conforms to Codominant Inheritance
S. L. Ewart, D. T. Ramsey, J. Xu, and D. Meyers
Anterior segment dysgenesis syndrome occurs frequently in Rocky Mountain horses and has two distinct ocular phenotypes: (1) large cysts originating from the
temporal ciliary body or peripheral retina and (2) multiple anterior segment anomalies including ciliary cysts, iris hypoplasia, iridocorneal adhesions and opacification, nuclear cataract, and megalocornea. To determine if anterior segment dysgenesis syndrome is heritable in horses we performed ophthalmic examinations
and collected pedigree information on horses (n 5 516) in an extended Rocky
Mountain horse pedigree. Logistic regressive segregation analysis of a subset of
animals (n 5 337) in which the ocular phenotypes of progeny and both parents
were known indicated that the codominant inheritance model best fit the data. This
model predicted cyst phenotype expression in heterozygous animals and multiple
anterior segment anomalies in homozygous animals. Several cases of nonpenetrance of the cyst phenotype were detected in one lineage. The close resemblance
between the inheritance and lesions observed in Small eye mice and rats, humans
with congenital aniridia or anterior segment malformation, and horses with anterior
segment dysgenesis syndrome supported the conclusion that anterior segment
dysgenesis syndrome in the horse may be homologous to similar ophthalmic
anomalies in other species.
From the Departments of Large Animal Clinical Sciences ( Ewart) and Small Animal Clinical Sciences (Ramsey), College of Veterinary Medicine, Michigan State
University, East Lansing, Michigan 48824, and the Center for the Genetics of Asthma and Complex Diseases,
University of Maryland, Baltimore, Maryland ( Xu and
Meyers). This work was supported in part by grants
from the Harvey Fiege Genetic Research Fund, College
of Veterinary Medicine, Michigan State University, and
the Michigan Animal Health Foundation. The authors
thank Patrick Venta for thoughtful review of the manuscript and Carrie Begin, Kristi Patterson, and Julie
Vantine for technical assistance. Address correspondence to Susan L. Ewart at the address above or e-mail:
[email protected].
q 2000 The American Genetic Association 91:93–98
Genetic defects that result in heritable abnormalities can be a significant source of
morbidity within affected pedigrees. Animals in small breed registries are generally derived from small gene pools. Similarly gene pools can be selectively limited
by intensively breeding individuals with
desired characteristics. In these situations
the risk of propagating undesirable traits
is also amplified. This has been illustrated
recently in the quarter horse breed, where
selective and intensive breeding of one
blood line that carried a dominant mutation for a sodium channel defect resulted
in the widespread occurrence of the associated disease hyperkalemic periodic
paralysis ( HYPP) (Rudolph et al. 1992).
The Rocky Mountain horse is a new and
rapidly expanding pleasure horse breed
with a registry established in 1986. Many
Rocky Mountain horses descend from a
single foundation sire. We recently described an ophthalmic disease with two
distinct phenotypes in Rocky Mountain
horses (Ramsey et al. 1999). Large fluidfilled cysts arising from the temporal ciliary body and peripheral retina characterized one ocular phenotype detected in
this breed. The other phenotype was a
syndrome of multiple anomalies of the anterior segment consisting of ciliary and/or
retinal cysts, severe iris hypoplasia, iridocorneal adhesions, peripheral corneal
opacification, and nuclear cataract. Affected horses had abnormal pupillary light responses and pupils did not dilate after instillation of mydriatic drugs. Some of the
horses with multiple anterior segment
anomalies also had lens subluxation, focal
retinal detachment, microphthalmia, megalocornea, macropalpebral fissures, and
craniofacial abnormalities. These lesions
were congenital and occurred bilaterally
in the majority of cases. While individual
horses in this group demonstrated a variety of lesions of both the anterior and posterior ocular segments, all the abnormalities were consistent with dysgenesis of
the anterior segment as predicted embryologically (Cook 1989; Gruss and Walther
1992) and as described in humans ( Hanson et al. 1993, 1994), mice ( Hill et al.
1991; Walther and Gruss 1991), and rats
( Fujiwara et al. 1994; Matsuo et al. 1993).
Thus we refer to this complex ocular phenotype in the horse as anterior segment
dysgenesis (ASD), and to the composite
disease, which includes cysts and ASD le-
93
sions, as the ASD syndrome (Ramsey et al.
1999).
While there are no previous reports that
specifically investigate the potential familial inheritance of this ocular disease, it
was apparent to veterinarians who work
with Rocky Mountain horses that ocular
defects occur in this breed at a rate much
greater than that seen in other breeds.
The objective of the current study was to
determine whether the ocular lesions of
ASD syndrome are familial, and if so, to
characterize the mode of inheritance of
this disease. Segregation analysis of ocular
phenotypes and pedigree information
from 516 horses in an extended Rocky
Mountain horse family indicated that lesions of the ASD syndrome were inherited
in a codominant manner in these horses.
Methods
Study Population
The index case for this study was an 8year-old Rocky Mountain horse stallion,
VIII-124, that was referred to the university
teaching hospital for evaluation because
he had two generations of progeny that
were characterized by the referring veterinarian as having a high incidence of ocular lesions. Eight offspring in the first generation and six offspring in the second
generation had been previously noted to
have cataracts and purported vision impairment. We examined VIII-124 and six of
his progeny. In addition, we examined a
large population of Rocky Mountain horses residing in several states in the Midwest ( Illinois, Indiana, Kentucky, Michigan, Missouri, and Ohio). Examined
horses were located on 30 farms that
housed primarily Rocky Mountain horses.
To avoid ascertainment bias, all horses
present on each farm were examined, with
the exception of five horses on farm C that
had been previously examined by another
ophthalmologist, and approximately 20
horses on farm D that were not readily accessible. The small number of horses of
other breeds present on each farm were
examined when available. Five hundred
sixteen horses were examined consisting
of 342 females and 174 males. The ages of
the examined animals ranged from 10 h to
29 years.
Clinical Examination
Horses were examined for general physical abnormalities. The colors of the coat,
mane, and tail were documented. Detailed
ophthalmic examinations were performed
in a darkened room before and after pu-
94 The Journal of Heredity 2000:91(2)
pillary dilation. One percent tropicamide
was instilled into the conjunctival fornix
to effect pupillary dilation. Ophthalmic examination included direct, focal, and diffuse slit lamp biomicroscopy, applanation
tonometry, and indirect ophthalmoscopy.
Pedigree Structure
Pedigree information was obtained for
each horse in the form of a breed association certificate of registration that contained the identification, gender, birthdate, color, markings, and up to four
generations of parentage. Based on this information, detailed multigenerational pedigrees were constructed. The study population of 516 horses spanned nine
generations of an extended family. Pedigree information alone was available on an
additional 232 horses extending back four
more generations, so that the completed
pedigree contained 748 horses in 13 generations.
Segregation Analysis
All pedigrees were inspected for evidence
of inheritance of ophthalmic abnormalities. Formal segregation analysis was performed on a subset of 337 individuals in
26 families in which offspring and both
progenitors were examined. Multiple inheritance models were tested for goodness-of-fit via logistic regression ( Bonney
1986) using the Statistical Analysis for Genetic Epidemiology program procedure
REGD (SAGE 1994). Tested models included Mendelian (dominant, codominant, and
recessive), environmental, and sporadic
models. Comparisons were made between
each inheritance model and the general
(unrestricted) model to determine whether the restrictions placed on a model significantly decreased its likelihood. If the
likelihood of a model differed significantly
by chi-square analysis from the likelihood
of the general model, the model was rejected. In Mendelian transmission the
probability that a parent of type u transmits allele A to the offspring is tAA 5 1, tAB
5 0.5, and tBB 5 0 for u 5 AA, AB, and BB.
In our analysis the transmission parameters t for the general model were tAA 5 0.9,
tAB 5 0.6, and tBB 5 0. Significant difference from the general model was assigned
at P , .05. Penetrance estimates were obtained from the formula
P(u) 5 eb/1 1 eb
where P is the penetrance of genotype u
for u 5 AA, AB, or BB, and b is the baseline parameter (SAGE 1994).
Results
Clinical Examination
Horses were classified on the basis of ophthalmic examination. Approximately half
of the horses examined (250/516) had one
or multiple large, translucent cysts arising
from the temporal ciliary body and/or peripheral retina ( Figure 1a). A smaller
group of horses (72/516) had ASD, as characterized by multiple abnormalities of the
cornea, iris, lens, and iridocorneal drainage angle ( Figure 1b,c). Two horses had
anterior uveitis, but no cysts or ASD. The
remaining horses had normal eyes (192/
516). Horses with ASD lesions always had
cysts. These results indicated that two
distinct anomalous ocular phenotypes,
cysts and ASD, occurred consistently and
reproducibly in Rocky Mountain horses.
The uniformity of observed lesions
throughout a large population of Rocky
Mountain horses suggested a common
cause for these abnormalities.
Pedigree Structure
Pedigree information was available for all
516 horses examined. Pedigree information obtained from the registration papers
of the unexamined horses was also used
for the purposes of constructing genealogies. The final pedigree contained 748
horses in 13 generations. Offspring and
both progenitors were examined in 26 families composed of 337 individuals ( Table
1).
One stallion ( IV-7) was noted to be present in the ancestry of a large number of
affected and unaffected horses in the extended pedigree, and 303 of the 322 horses
affected with cysts or ASD were reported
to descend from IV-7. The pedigrees of all
horses in the extended family were examined to determine the extent of common
ancestry: 372 horses could be traced to IV7 through one progenitor, 266 horses
could be traced to IV-7 through both progenitors, and 110 horses could not be definitively traced to IV-7. Horses examined
were in generations 5-13 of the pedigree or
were unrelated to IV-7. Seven first-generation offspring of IV-7 were examined and
found to have either cysts or normal eyes
( Figure 2). The index case, VIII-124, had
ASD lesions and was a fourth-generation
descendent of stallion IV-7 ( Figure 2). Five
of six offspring of VIII-124 had cysts and
one had normal eyes.
Segregation Analysis
The dominant, environmental, and sporadic models were rejected in the segregation
Figure 1. Ocular photographs of horses affected with ASD syndrome lesions. (a) A cyst of the temporal ciliary
body of the right eye is evident in the pupillary aperture. (b) Photograph of the iris of a horse with ASD. Iridial
hypoplasia is characterized by iris sheets and a circumferentially located, flattened granula iridica. The pupil is
also dyscoric. (c) Photomicrograph of the iris ( I) of a horse with ASD. The iris is hypoplastic and the granula
iridica is flattened. Note the dysplastic ciliary body epithelium and primitive and immature retinal tissue (arrows)
present on the posterior side of the iris. * indicates cornea.
analysis because the likelihoods of these
models differed significantly from that of
the general model based on the chi-square
test ( Table 2). The codominant model was
the most parsimonious model and its likelihood was not significantly different from
that of the general model. The likelihood
of the recessive model was also not different from that of the general model, however, it did not fit the data as well as the
codominant model. The codominant inheritance model predicted that the cyst
phenotype was expressed in heterozygous
animals and the ASD phenotype was expressed in homozygous animals.
The penetrance estimate for the cyst
phenotype was 60.35% for AB, 99.86% for
BB, and approached zero for AA. For the
ASD phenotype the penetrance estimate
was 99.87% for BB and approached zero
for AB and AA. Based on the hypothesis
that obligate heterozygotes should have
cysts, nonpenetrance was theorized in 10
unaffected offspring that derived from progenitors with ASD and 3 unaffected progenitors that produced offspring with ASD
( Figure 3). All but one ( VI-57) suspected
nonpenetrant cases could be traced to
stallion VI-38, who was a backcross progeny of the founder stallion ( Figure 2). Numerous additional descendants of VI-38
did not demonstrate altered penetrance of
Table 1. Phenotypes of progenitors and
offspring in 26 families with ASD syndrome
Sire n
Dam
n
AA
AA
0
AA
AB
2
AA
BB
0
AB
AA
65
AB
AB
61
AB
BB
18
BB
BB
BB
a
2
144
27
AA
AB
BB
11
16
0
Offspring n
AA
AB
BB
AA
AB
BB
AA
AB
BB
AA
AB
BB
AA
AB
BB
AA
AB
BB
AA
AB
BB
AA
AB
BB
AA
AB
BB
Expected
Perpercentcentage age a
100
2
100
50
50
100
33
28
4
14
20
27
50.8
43.1
6.2
23
32.8
44.3
50
50
10
8
6
5
55.6
44.4
54.5
45.5
100
2
9
5
12.5
56.3
31.3
50
50
25
50
25
50
50
100
Phenotypes: AA 5 unaffected, AB 5 cysts, BB 5 ASD.
The percentage of progeny expected in each category
based on a fully penetrant codominant inheritance
model.
Figure 2. Pedigrees demonstrating the relationship between the founder stallion ( IV-7), the proband ( VIII-124),
and the common ancestor for nonpenetrance of the cyst phenotype ( VI-38). A indicates horses that derive from
IV-7 where complete relationships are not shown for simplicity. Open symbols indicate unaffected subjects; halffilled symbols indicate subjects affected with cysts; solid symbols indicate subjects affected with ASD; symbols
enclosing question marks indicate unexamined subjects.
Ewart et al • Codominant Inheritance of Anterior Segment Dysgenesis in Horses 95
Table 2. Results from regressive logistic modeling (REGD) using 337 individuals in 26 families with ASD syndrome
t
Model
qA
General
Environmental
Codominant
Dominant
Recessive
Sporadic
.33
.69
.48
.65
.38
[1]
0.9
0.3
NA
NA
NA
NA
0.6
0.3
NA
NA
NA
NA
Cyst phenotype
0.0
0.3
NA
NA
NA
NA
ASD phenotype
bAA
bAB
bBB
bAA
bAB
bBB
22ln
df
x2
Pa
232.0
0.99
25.24
261.0
20.62
0.26
1.76
21.43
0.42
7.22
20.62
0.26
21.98
4.41
6.53
7.22
5.94
0.26
33.2
25.45
256.6
245.1
236.2
20.68
250.1
21.29
253.1
6.29
236.2
20.68
22.83
3.78
6.65
6.29
5.53
20.68
641.9
673.3
648.4
672.2
652.1
684.5
NA
2
3
5
5
11
NA
31.4
6.5*†
30.3
10.2*
42.6
10
8
7
5
5
2
qA 5 allele frequency for unaffected allele; t 5 transmission probability; b 5 baseline parameter for genotypes AA, AB, and BB; 22ln 5 22ln( likelihood); df 5 degrees of
freedom; Pa 5 number of parameters estimated; NA 5 not applicable for the given model.
* Codominant and recessive models were not significantly different from the general model at P , .05.
† Codominant model was the most parsimonious.
the cyst phenotype. In addition to common heritage through VI-38, progeny of select sires were particularly predisposed to
nonpenetrance. Stallion VII-50 had ASD
and yet produced 4 foals with normal oc-
ular phenotypes ( Figure 3a), along with 12
foals with cysts, and 8 foals with ASD
(data not shown). Similarly, stallion X-107
had ASD and produced five foals with normal eyes ( Figure 3b), six foals with cysts,
and no foals with ASD (data not shown).
Stallion VIII-124, the index case, had ASD
and produced one foal with a normal ocular phenotype ( Figure 3a), five foals with
cysts, and no offspring with ASD (data not
shown). Nonpenetrance was also suspected in several phenotypically unaffected
horses based on their production of offspring with ASD. Phenotypically unaffected mares VI-57 and IX-5 were each bred to
multiple stallions (total of six matings with
six stallions) and five of the mating produced progeny with ASD ( Figure 3b). Nonpenetrance in the two mares was hypothesized to be more likely than phenocopy
in the five offspring due to the repeated
nature of the event in each mare. While
mare VI-57 was a descendent of the founder stallion, she was not a descendent of
VI-38, however, three of the four stallions
she was bred to did derive from VI-38. It
is more difficult to support either nonpenetrance or phenocopy hypotheses in
horse X-42, who had ASD and was the
progeny of an unaffected mare, IX-30, and
an unexamined stallion, IX-90 ( Figure 3b).
In contrast, nonpenetrance was strongly
suggested in horse VIII-134, a phenotypically unaffected mare derived from a sire
with ASD ( VII-50), as VIII-134 was mated to
a stallion with cysts ( IX-24) and subsequently produced a male offspring with
ASD ( X-83) ( Figure 3a).
Discussion
Figure 3. Nonpenetrance of the cyst phenotype traced to a common ancestor ( VI-38) and predisposition for
nonpenetrance was further clustered in select families. Nonpenetrant cases are denoted by *. A indicates horses
that derive from IV-7 and B indicates horses that derive from VI-38 where complete relationships are not shown
for simplicity. (a) Nonpenetrance of the cyst phenotype in four normal progeny of a stallion with ASD ( VII-50) and
one normal offspring of the proband ( VIII-124). Other progeny of these stallions together include 17 offspring with
cysts and 7 offspring with ASD (data not shown). (b) Nonpenetrance of the cyst phenotype in five normal offspring
of a stallion ( X-107) with ASD. X-107 also produced six offspring with cysts (data not shown). Mare IX-5 was
classified as nonpenetrant as she had normal eyes and yet produced two foals with ASD. Mare VI-57 had normal
eyes and did not descend from VI-38, however, she produced three offspring with ASD and one with cysts. Open
symbols indicate unaffected subjects; half-filled symbols indicate subjects affected with cysts; solid symbols indicate subjects affected with ASD; symbols enclosing question marks indicate unexamined subjects.
96 The Journal of Heredity 2000:91(2)
Our results support the hypothesis that
the ophthalmic lesions of cysts and ASD
in Rocky Mountain horses were inherited
in a codominant manner with cysts expressed in the heterozygous state and
complex ASD lesions expressed in the homozygous state. Nonpenetrance of the
cyst phenotype appeared to occur in a
small number of cases and was associated
with a select lineage. A large proportion of
the 516 examined horses was affected
with one of the disease phenotypes, as 250
horses (48.5%) had retinal or ciliary body
cysts and 72 horses (14.0%) had ASD. Our
assessment of the prevalence, epidemiology, and genetic model fitting of this disease in Rocky Mountain horses provides
the first documented evidence of the heritability of the ASD syndrome in horses.
Striking similarities are present between
the ocular and craniofacial lesions observed in Smalleye (Sey) mice and rats
( Fujiwara et al. 1994; Hogan et al. 1986),
humans with congenital aniridia or malformation of the anterior segment (Glaser et
al. 1994; Hodgson and Saunders 1980), and
horses with ASD syndrome ( Figure 1).
Based on our observations, we hypothesize that the lesions of the ASD syndrome
in the horse may be homologous to Sey in
mice and rats, and to congenital aniridia
in humans. We predict that complete loss
of gene function in the horse does not occur from the proposed mutation, based on
our observations of comparably mild phenotypes in Rocky Mountain horses.
Pedigree analysis of a large number of
Rocky Mountain horses with ASD syndrome indicated that stallion IV-7 was
common in the ancestry of 303 of 322 affected horses. This raised the possibility
that IV-7 carried a mutant allele at the locus encoding the gene causing ASD syndrome, and extensive propagation of this
genotype through inbreeding resulted in
widespread distribution of this disease.
Horse IV-7 was deceased, and therefore it
was not possible to determine his ocular
status. Horse IV-7 was common in the ancestry of both affected and unaffected
horses and is considered a foundation sire
for the breed. Because of the frequency of
his lineage in the population, we could not
determine if he was also a founder of this
disease. However, based on the presence
of the cyst phenotype in five of the seven
examined first-generation progeny of IV-7,
it was clear that he carried the mutant allele.
We observed no matings between two
known unaffected progenitors. This appeared to be related to the high incidence
of ocular lesions in stallions selected for
breeding. An ascertainment bias toward
affected families was not supported, as essentially all horses present at each farm
were examined. Ocular phenotypes could
not be predicted by external observation
alone, therefore owners were not aware of
their horses’ ocular phenotypes prior to
clinical examination.
Our findings of a small number of phenotypically unaffected horses deriving
from progenitors with ASD, as well as un-
affected horses producing progeny with
ASD, confound the codominant inheritance hypothesis. We propose that these
cases are the result of nonpenetrance of
the cyst phenotype, which may be due to
epistatic interactions between a modifier
gene and the susceptibility locus or to environmental influence. Twelve of 13 cases
of suspected nonpenetrance shared VI-38
as a common ancestor. However, numerous additional progeny of VI-38 did not
demonstrate altered expression of the
cyst phenotype. Stallion VI-38 was a son of
the foundation stallion produced by a
backcross mating ( Figure 2). The nonpenetrant cases tended to be clustered in
their occurrence. Furthermore, along with
their identifying progenitors or progeny,
they were located on eight different farms
at the time of examination. Thus the presence of a modifier gene acting epistatically
with the susceptibility locus to alter disease expression seemed more likely than
indeterminate
environmental
factors.
There was a high rate of consanguinity in
the pedigrees we studied. Thus while the
majority of nonpenetrant cases traced to
VI-38, many descendants of VI-38 also
traced to the foundation stallion through
one or more of his other offspring. Finding
nonpenetrance in mare VI-57, who did not
descend from VI-38, suggested that modifier genes may not exist exclusively in one
branch of the lineage. Furthermore, the
high rate of consanguinity made it virtually impossible to definitively localize the
origin of a modifier gene to VI-38, despite
the fact all but one case with evidence for
nonpenetrance shared this common ancestor.
Iris hypoplasia in the horse has been
previously described in two pedigrees. Eriksson (1955) described aniridia in 109
Belgian horses that derived from a common sire. The ocular phenotype had a
dominant mode of inheritance and was
characterized by bilaterally large, circular
pupils that were nonreactive to light. Progressive lens opacity was also present in
a variable number of horses. Joyce et al.
(1990) reported that a quarter horse stallion and seven offspring had iris hypoplasia, large, round, and fixed pupils, absence
of corpora nigra, and limbal dermoids.
One additional offspring had normal eyes.
The ocular lesions in these Belgians and
quarter horses were distinct from those
present in our study population of Rocky
Mountain horses.
Inherited ophthalmic defects similar to
those found in our horse pedigrees have
been reported in mice, rats, and humans
(Churchill and Booth 1996; Fujiwara et al.
1994; Hogan et al. 1986). Small eye (Sey) is
a codominant mutation that causes decreased eye size and delayed closing of
the optic cup in mice heterozygous for
this mutation. In homozygous animals, Sey
causes anophthalmia and lack of nasal primordia ( Hogan et al. 1986). Mice homozygous for Sey die shortly after birth, most
likely the result of undeveloped nasal cavities. The rat Small eye strain (rSey) is similar phenotypically to the Sey mouse, as
heterozygous rats have small eyes while
eyes and nose are lacking in homozygous
animals ( Fujiwara et al. 1994). Mutations
in the Pax6 gene are reported to cause Sey
in mice ( Hill et al. 1991) and rats (Matsuo
et al. 1993).
Congenital aniridia and anterior segment dysgenesis in humans are ocular
phenotypes with considerable overlap between them. Aniridia is an inherited congenital malformation in humans characterized by severe iris hypoplasia. The term
aniridia is a misnomer because aniridia is
a panocular disorder and is typically associated with cataracts, retinal and ciliary
body hypoplasia, and corneal opacification ( Hanson et al. 1993; Nelson et al.
1984). There is considerable variation in
expression of the congenital aniridia phenotype, but the manifestations appear to
be symmetrical ( Hodgson and Saunders
1980). Diseases of anterior segment dysgenesis in humans are characterized by
multiple malformations of the ocular anterior segment and often occur with corneal opacity, microphthalmos, cataract,
and dysgenesis of the iris and iridocorneal
angle. The variable expression of ocular
lesions associated with congenital aniridia
and anterior segment dysgenesis in humans is consistent with our findings in the
horse in which some lesions were present
in all cases (ciliary and/or retinal cysts,
iris hypoplasia, iridocorneal adhesions,
dyscoria, peripheral corneal opacification,
and nuclear cataract), while the presence
of other lesions ( lens subluxation, focal
retinal detachment, microphthalmia, megalocornea, macropalpebral fissures, and
craniofacial abnormalities) varied between cases.
Anterior segment dysgenesis mutations
may occur spontaneously in humans or
they may be familial with variable inheritance patterns (Cook 1989; Holmström et
al. 1991). The congenital aniridia phenotype in humans is generally reported to be
a dominant trait caused by mutations in
the PAX6 gene (Glaser et al. 1994; Schedl
et al. 1996). Matings are rarely seen be-
Ewart et al • Codominant Inheritance of Anterior Segment Dysgenesis in Horses 97
tween two people affected by this trait,
therefore offspring potentially homozygous for congenital aniridia are rare. Until
a sufficient number of humans who are homozygous for PAX6 mutations are studied,
it will remain unclear whether the trait is
truly dominant or, like in mice and rats,
whether a more severe phenotype occurs
in the homozygous condition ( Hodgson
and Saunders 1980). However, the limited
number of reports of matings between humans with congenital aniridia present in
the literature suggest that homozygous
PAX6 mutations may be lethal ( Elsas et al.
1977; Grove et al. 1961; Hodgson and Saunders 1980). For example, a consanguineous couple with congenital aniridia had
six pregnancies producing one female
child with congenital aniridia, three male
children who died within 24 h of birth, and
two miscarriages. No documentation of
ocular phenotypes was available on the
five deceased children (Grove et al. 1961).
Another consanguineous couple with congenital aniridia had three children with
congenital aniridia and one stillborn child
for which there was no documentation of
the ocular phenotype ( Elsas et al. 1977).
A nonconsanguineous mating in a couple
with congenital aniridia produced a stillborn fetus with complete absence of eyes,
nose, and adrenal glands ( Hodgson and
Saunders 1980).
In conclusion, we report that the ASD
syndrome is familial in Rocky Mountain
horses and is best fit by the codominant
inheritance model. Penetrance was not
complete for the cyst phenotype and nonpenetrance was clustered in one lineage.
The striking similarities between the ocular and craniofacial phenotypes of horses
with ASD syndrome, Sey in mice and rats,
and humans with congenital aniridia or
anterior segment malformations, as well
98 The Journal of Heredity 2000:91(2)
as the codominant mode of inheritance of
these lesions in horses, mice, rats, and potentially in humans, support the hypothesis that the lesions of the ASD syndrome
in the horse are homologous to Sey in
mice and rats, and to congenital aniridia
or anterior segment malformation in humans. The similarities and subtle differences between the horse and human regarding the dysgenesis of the anterior
segment make the ASD syndrome in the
horse a potentially rewarding disease
model for humans.
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Received July 29, 1999
Accepted October 18, 1999
Hanson IM, Fletcher JM, Jordan T, Brown A, Taylor D,
Corresponding Editor: Stephen J. O’Brien