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Clinical and Experimental Ophthalmology 2014; 42: 412 doi: 10.1111/ceo.12149

Review
Corneal dystrophies and genetics in the
International Committee for Classication
of Corneal Dystrophies era: a review
Andrea L Vincent FRANZCO
Department of Ophthalmology, National Eye Centre, Faculty of Medical and Health Science, University of Auckland, Auckland,
New Zealand

ABSTRACT
Many of the corneal dystrophies have now been
genetically characterized, and a system was established
in 2008 by The International Committee for Classification of Corneal Dystrophies (IC3D) in an attempt to
standardize the nomenclature. IC3D provided a classification system whereby all dystrophies can be categorized on the basis of the underlying genetic knowledge.
Since that time, further work has established even
more phenotypic and allelic heterogeneity than anticipated, particular for Fuchs endothelial corneal dystrophy and posterior polymorphous dystrophy. Using
genome-wide association studies, a number of genes
are now implicated both in normal corneal quantitative traits, such as central corneal thickness, as well as
in disease. There is also a trend towards functional
characterization of the genetic variants involved to
elucidate the pathophysiology of these entities. This
review article will provide an overview of the knowledge to date, with an emphasis on findings since the
IC3D classification was published in 2008.
Key words: corneal dystrophy, genetic disease, genetics, molecular genetics.

INTRODUCTION
Heralded by the completion of sequencing the
human genome, the last decade has seen an expo-

nential increase in gene identification for many

human diseases. For eye diseases, much progress has
been made, most notably with the inherited retinal
dystrophies, but many of the corneal dystrophies
have also now been genetically characterized. As the
ability to genotype became more accessible, and
faster, and the associated costs reduced, many different groups around the world have embarked on
genotyping projects. The International Committee
for Classification of Corneal Dystrophies (IC3D) was
established and published a comprehensive reference document in 2008.1 Since then, further work
and different tools for probing the genetic environment have identified more genes involved in the
inherited corneal dystrophies, and other genes
involved with normal corneal variation, such as
central corneal thickness. This review article will
review the knowledge to date, with an emphasis on
new genetic mechanisms identified since the IC3D
article in 2008.
From the earliest genetic investigations involving corneal dystrophies, it initially became apparent
that significant subgroups of the corneal dystrophies
were in fact manifestations of mutations within the
same gene. Previously once considered to be distinct
discrete entities, genotyping showed that they actually represented a spectrum of disease.
The transforming growth factor-beta induced
(TGFBI) dystrophies, in particular, illustrate this point
clearly. Granular type I, lattice and Avellino were, in
the pregenomic era, considered to be separate entities based on appearance, symptoms, age of onset,

Correspondence: Dr Andrea L Vincent, Department of Ophthalmology, National Eye Centre, Faculty of Medical and Health Science, University of
Auckland, Private Bag 92019, Auckland, New Zealand. Email: a.vincent@auckland.ac.nz
Received 10 April 2013; accepted 6 June 2013.
Competing/conflicts of interest: No stated conflict of interest.
Funding sources: Save Sight Society of New Zealand, Aukland Medical Research Foundation, Maurice and Phyllis Paykel Trust, University
of Auckland.
2013 Royal Australian and New Zealand College of Ophthalmologists

Corneal dystrophies and genetics

histology and recurrence after penetrating keratoplasty. Linkage was initially established for all three
dystrophies to the 5q locus.2 Subsequent genotyping has proven that they are in fact all part of the
TGFBI genotypic spectrum, albeit distinct genotype
phenotype entities.3 Many publications have now
clearly shown that the remainder of the TGFBIassociated cases represent intermediaries, as illustrated with the H626P mutation,4 with features of
both the Reis-Buckler and the Thiel-Behnke phenotypes, yet with features not classically representative
of the previously described criteria for the distinct
subtypes of dystrophies. These findings give strength
to the concept of a spectrum or continuum of phenotypic expression.
This has, however, lead to difficulties with
nomenclature and classification should the dystrophy continued to be called the eponymous name
given in the 19th or early 20th century, even though
several versions of a name for that dystrophy exist
based on historical overlap and language barriers.
Alternatively, should the dystrophy be classified
by the underlying biochemical defect or structural
anomaly, or perhaps by its clinical appearance, or
rather by the causative genetic defect? For example,
Groenouw dystrophy is still variably called Groenouw, granular dystrophy, classic, granular corneal
dystrophy type 1 or a TGFBI dystrophy associated
with mutation R555W or R124S. Historically, when
researchers in different parts of the world were
working on similar dystrophies, there was no
common language to describe the dystrophies, and to
ensure that they were even talking about the same
dystrophy historical evidence points to a permutation in the description of Reis Buckler dystrophy
compared with Thiel-Behnke, which appears to
have overlapped, and the descriptors confused
between the two entities in the literature for a
number of years,5 suggesting eponymous names
have shortcomings.

IC3D CLASSIFICATION
In order to try and standardize the nomenclature, and
create a universal system for classification, a committee was established the IC3D consisting of
corneal subspecialists from many different countries.
These experts came together to create a consensus
document. This was published in 20081 and attempts
to create a standardized nomenclature for each dystrophy, as well as a grading system depending on
whether the underlying genetic defect is known, a
loci known, evidence for a genetic cause suspected or
unknown. That document remains to date a comprehensive review of the genetics of corneal dystrophy
as documented at the end of 2008. Therefore, without
reiterating that information, this article will review

5
the classification system used, and look at how this
information is put to use, and the advancements
in corneal dystrophy genetics since then. One area
in particular that has led to advancements is the
genome-wide association study (GWAS) (discussed
in greater detail later) and a trend towards characterization of the functional effect of genetic variation.
The IC3D classification uses four distinct categories based on phenotype and genotype, and placed
known corneal dystrophies into a given category. A
category 1 dystrophy is one that is well defined, the
gene has been mapped and identified and specific
mutations in that gene are known. The TGFBI group
of dystrophies fit into this category. Granular corneal
dystrophy type 1 is now the official title for the entity
mentioned earlier; however Avellino corneal dystrophy, predominantly associated with the R124H
mutation in TGFBI, is now officially designated
granular corneal dystrophy type 2 (granular-lattice),
and the other alternative yet perhaps more descriptive name, combined granular-lattice corneal dystrophy, is also out of favour.
Category 2 is reserved for those in which a specific
chromosomal locus (or loci) has been mapped for a
well-defined corneal dystrophy, but the underlying
gene is not yet identified. An example would be the
Thiel-Behnke corneal dystrophy (which retains its
eponymous title TBCD). This was mapped to chromosome 10q23-24,6 but no gene yet identified.
Similarly, with the posterior polymorphous corneal
dystrophy (PPCD) 1 locus on chromosome 20p,
when mutations in visual system homeobox 1 gene
(VSX1) were initially characterized,7 the gene sat
within the originally mapped PPCD1 locus,8 but
when the locus was further refined in a Czech population, VSX1 actually sat outside the locus.9 It has
subsequently been excluded as the causative gene in
the pedigrees that have linked to that locus.1012
Category 3 is reserved for well-characterized and
well-defined corneal dystrophies, although one in
which no linkage/loci have yet been elucidated.
A number of pedigrees with unique anterior membrane corneal dystrophies have been described
including our previous work13 in which we excluded
known genes and loci by a combination of mutational analysis and linkage. To move a category 3
dystrophy to the level of category 2 can now, in
theory, be relatively more easily achieved using a
genome wide scan with a single-nucleotide polymorphism (SNP) microarray to establish a clear
chromosomal locus. Once a locus (or loci) is identified, next-generation sequencing within this linked
region(s) can be used to establish gene identification.
Ideally, further families with similar phenotypes and
autosomal dominant inheritance will be identified
and can be tested against any putative gene of interest
within this region, identified from the genome-wide

2013 Royal Australian and New Zealand College of Ophthalmologists

Vincent

scan, which segregates with the disease, makes biological sense and is expressed in the eye.
The final category, category 4, is essentially for
all other dystrophies, suspected new, or previously
documented, corneal dystrophy, although the evidence for it being a distinct entity is not yet convincing. One example is the central cloudy dystrophy of
Franois. The IC3D rationale for naming this a category 4 dystrophy is that in many of the reports,
there is no documentation of familial inheritance,
and therefore, it is feasible these cases were actually
posterior crocodile shagreen.

Identication of outliers
The molecular investigation of a diverse spectrum of
corneal phenotypes investigated in large and small
population cohorts alike has shown the ability to
identify outliers, that is, those with features, or even
slightly atypical features of a given genotype or
syndrome/dystrophy, yet (i) either do not carry
mutations within the known gene, opening the door
for identification of alternative molecular mechanisms, or (ii) the corneal phenotype may actually be
a manifestation of a systemic disorder. An atypical
lattice dystrophy observed prior to a diagnosis of a
heavy chain amyloidosis is an example.14 A 61-yearold male with no family history ocular history presented with contact lens intolerance and noted to
have a bilateral, atypical, fine, midperipheral lattice
corneal dystrophy with minor central subepithelial
scarring. (Fig. 1). TGFBI mutational analysis was
unremarkable. Two years later when he presented
with nephrotic syndrome Gelsolin (GSN) analysis
was undertaken and was also unremarkable. Renal
biopsy showed amyloid deposition, which on direct
protein sequencing by mass spectrometry was demonstrated to be heavy-chain deposition rather than
the more usual light-chain deposition. This demonstrates the utility of gene testing, when a negative
gene test should alert one to consider other atypical
diagnoses.

and distinct phenotypegenotype correlations have

occurred His626Arg mutation is the underlying
cause for over 75% of the lattice observed in Vietnamese patients.17 This lattice has a later onset, with
fewer and thicker lattice lines as well as asymmetry,
compared with the classic lattice. This manifestation
is rarely described outside this ethnic group.
Recently, founder mutations and haplotypes suggest a common underlying genetic defect as witnessed in the Czech population with PPCD1.12 A
common haplotype in nine Czech families with PPCD
segregated with the PPCD1 locus, which, by using
linkage disequilibrium mapping, inferred an ancestral locus in which the appearance of the causative
mutation was able to be dated to between 64 and 133
generations back and is the cause for PPCD in 14
unrelated families. The underlying genetic defect on
20p11.23 to date defies characterization, as the one
gene in the interval, zinc finger protein 113 (ZNF113),
was extensively probed for mutations and copy number variations in coding and untranslated regions.

De novo mutations
Lack of a family history, particular in autosomal
dominant conditions, does not exclude heritability
a number of de novo mutations have been described
with the TGFBI-associated dystrophies,4,18,19 with
somatic mosaicism also thought to contribute to this
finding.20

Population specic disease

The genetic investigation of corneal dystrophies in
smaller ethnically diverse countries, in addition to
the usual large cohorts, has contributed to the literature in this field. Collectively, this research has
revealed other variants of disease manifestation not
previously realized. Traditionally, this group of disorders is considered bilateral. However, it is clear
that clinical manifestations may include a very asymmetrical presentation as described with atypical and
asymmetric lattice dystrophies associated with the
His572del mutation15 and the Val624Met mutation.16
Within certain ethnic groups, a number of clear

Figure 1. Slit-lamp photograph of subjects cornea demonstrating scattered subepithelial opacication and ne branching
lattice lines (arrow heads).

2013 Royal Australian and New Zealand College of Ophthalmologists

Corneal dystrophies and genetics

Table 1. Genetic/allelic heterogeneity. This table lists two corneal dystrophies Fuchs endothelial corneal dystrophy (FECD) and posterior polymorphous corneal dystrophy (PPCD) for which more than one causative genetic mechanism has been identied
Corneal dystrophy
FECD

PPCD

Locus
FECD1
FECD2
FECD3
?
FECD4
FECD5
FECD6
FECD7
SVD
PPCD
PPCD1
PPCD2
PPCD3
Other

Location
1p34.3p32.3
13pterq12.13
18q21.2q21.3
18q12q21
20p13p12
5q33.1q35.2
10p11.2
9p24.1p22.1
2q37.1
20p11.23
20p11.2
1p34.3p32.3
10p11.2
2q36q37

Gene
COL8A2
unknown
(TCF4)
LOXHD1
SLC4A11
unknown
ZEB1
unknown
KCNJ13
unknown
VSX1
COL8A2
ZEB1
COL4A3

Reference
23

MIM
34

Biswas et al. Kobayashi et al.

Sundin et al.24
Baratz et al.47
Riazuddin et al.58
Riazuddin et al.53
Riazuddin et al.25
Riazuddin et al.36
Riazuddin et al.36
Hejtmancik et al.46
Liskova et al.12
Heon et al.7
Biswas et al.23
Krafchak et al.21
Krafchak et al.21

136 800
610 158
613 627
613 072
613 268
613 269
613 270
613 271
193 230
122 000
1220 000
609 140
609 141
120 070

COL4A3, collagen, type IV, alpha 3; COL8A2, collagen, type VIII, alpha 2; KCNJ13, potassium inwardly-rectifying channel, subfamily J,
member 13; MIM, mendelian inheritance in man; LOXHD1, lipoxygenase homology domains 1; SLC4A11, solute carrier family 4, sodium
borate transporter, member 11; SVD, snowake vitreoretinal degeneration; TCF4, transcription factor 4; VSX1, visual system homeobox
1; ZEB1, zinc nger E-box binding homeodomain 1.

Similarly in PPCD3, this feature has also been

documented,21,22 allowing an estimate of the de novo
mutation rate in zinc finger E-box binding homeobox
1 (ZEB1) leading to PPCD3 of at least 14%, not including pedigrees with reportedly unaffected parents but
no molecular genetic investigation undertaken.
However, with no prior family history, one still
must consider the other possibilites of incomplete
penetrance and false paternity.

Allelic and phenotypic heterogeneity

Greater allelic heterogeneity than anticipated is also
apparent is some entities such as PPCD (Table 1).
With a small number of changes observed in VSX17
and collagen, type VIII, alpha 2 (COL8A2),23 TCF8/
ZEB121,2628 remains the main contributor, but at
least 50% of affected individuals remain uncharacterized. Haplotype analysis in the Czech population
points to an as yet unidentified gene at the PPCD1
locus.12 Careful ocular phenotyping also suggests
that increased corneal steepening is a common
feature of PPCD corneas, likely regardless of the
underlying molecular genetic cause.29,30
A similar corneal dystrophy, posterior amorphous
corneal dystrophy was classified category 3 in IC3D,
with a question as to whether this is a dysgenesis
rather than dystrophic. However, an autosomal
dominant pedigree investigated have permitted
linkage to 12q21.33 with a LOD of 5.6. Although
excellent candidate genes existed within this region,
(Keratocan (KERA), Lumican (LUM), Decorin (DCN)
and Epiphycan (EPYC)) no mutations were identified. This finding moves posterior amorphous
corneal dystrophy to category 2.31

Further investigation of these genes also demonstrates the interplay with allelic and phenotypic
heterogeneity (Table 2). Although COL8A2 was initially described as one molecular cause of PPCD
(PPCD2),23 it was then also demonstrated to play a
role in FECD.34 The role of ZEB1 has expanded to be
causative of FECD6 in a small number of cases.35,36
The mutations in ZEB1 associated with the late onset
FECD are missense compared with the truncating and nonsense mutations observed in ZEB1
in PPCD3. A missense mutation is also described in
keratoconus.37 VSX1 continues to be implicated in
both PPCD and keratoconus, although a minor
player.38

Environmental factors
Environmental triggers such as laser in situ keratomileusis have been documented to precipitate
previously undiagnosed GCD2 post-laser in situ
keratomileusis, especially in the Korean population,39 emphasizing the importance of careful ocular
examination and family ocular history in the preoperative assessment. Feasibly, a genetic screen could
be undertaken as part of a routine work-up now that
the costs of testing have reduced, particularly with
the ease of which DNA can be obtained using saliva
collection kits, such as Oragene (DNA Genotek,
Ottawa, ON, Canada).

Non-ocular phenotype
Careful phenotyping of non-ocular features looking away from the eye may also reveal clues as to
the underlying pathology, as in PPCD associated

2013 Royal Australian and New Zealand College of Ophthalmologists

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Table 2. Phenotypic heterogeneity. This table highlights genes elucidated for the corneal dystrophies, and discussed in this review,
which demonstrate phenotypic heterogeneity and the corneal phenotypes with which they have been associated
Gene

Location

SLC4A11

20p13p12

VSX1

20p11.21

ZEB1

10p11

COL8A2

1p34.3

Locus
FECD4
CHED2
CDPD
PPCD1
KTCN1
CAASDS
PPCD3
FECD6
KTCN
PPCD2
FECD1

Phenotype
FECD
CHED-autosomal recessive
Harboyan syndrome
PPCD
Keratoconus
Craniofacial anomalies and anterior
segment dysgenesis
PPCD
FECD
Keratoconus
PPCD
FECD

Reference
32

MIM

Vithana et al.
Vithana et al.54
Desir et al.60
Heon et al.7
Heon et al.7
Mintz-Hittner et al.33

613 268
217 700
217 400
122 000
148 300
614 195

Krafchak et al.21
Riazuddin et al.36
Muszynska et al.37
Biswas et al.23
Biswas et al.23

609 141
613 270
609 140
136 800

CAASDS, craniofacial anomalies and anterior segment dysgenesis; CHED, congenital hereditary endothelial dystrophy; COL8A2,
collagen, type VIII, alpha 2; FECD, Fuchs endothelial corneal dystrophy; KTCN1, keratoconus 1; MIM, mendelian inheritance in man; PPCD,
posterior polymorphous corneal dystrophy; SLC4A11, solute carrier family 4, sodium borate transporter, member 11; VSX1, visual system
homeobox 1; ZEB1, zinc nger E-box binding homeodomain 1.

with ZEB1/TCF8 mutations; a higher incidence of

soft tissue abnormalities including hernias and
Dupuytren contracture are reported to occur.21,26,28
Further investigation into the role of ZEB1 in the
pathophysiology of PPCD3 reveals that it binds to a
promoter of the collagen, type IV, alpha 3 (COL4A3)
gene. Yellore and colleagues suggested that when
ZEB1 is mutated, there is alteration of either the
amount of expression or the temporal expression of
the COL4A3 protein.40 This in turn may influence the
endothelial cell to manifest a different phenotype.40
Interestingly, four genome-wide association studies (GWAS) have also associated the 10p11.22
locus, where ZEB1 resides, to obesity.4144 In mice
heterozygous for Zeb1 (Tcf8 +/-), the regulatory
effect of ZEB1 on the accumulation of adipose tissue
has been demonstrated.45
The body mass index of all individuals with PPCD
therefore is theoretically a useful adjunct in the phenotypic work-up, but in our study the body mass
index calculations were in the normal range.22

Fuchs endothelial dystrophy

Fuchs endothelial corneal dystrophy (FECD) remains one of the most common conditions requiring
corneal transplantation, and although rare genetic
variants identified are associated with both the
earlier onset and later onset subtypes, the majority
also remains without molecular classification. Much
progress has been made in the last 5 years (Table 1).
When the IC3D classification system was published,
only mutations in COL8A2 had been described
in early-onset disease. Other loci implicated at
that time were located at 13pTel-13q12.13, 15q,
18q21.2-q21.32 and a further locus for the early-

onset variant at 1p34.3-p32. A mutation in the gene

potassium inwardly-rectifying channel, subfamily J,
member 13 (KCNJ13) is described in one family with
snowflake vitreoretinal degeneration in which FECD
was part of the ocular phenotype.46
In 2010, a GWAS reported that two alleles present
in the transcription factor 4 (TCF4) gene encoding the
E2-2 protein increased the risk of developing FECD
by up to 30 times in those with homozygous allelles.47 This finding was quickly replicated in other
FECD populations.48,49 In particular, the TGC trinucleotide repeat expansion in TCF4 is strongly associated with FECD, and a repeat length >50 is highly
specific for the disease50 and a predictor of disease
risk. Further studies have strengthened the association of TCF4 polymorphisms in the FECD disease
process51,52 and also suggests a role for clusterin and
TGFBI polymorphisms.52 In the Australian FECD
cohort, immunohistochemistry showed differential
expression of clusterin and TGFBI proteins in FECDaffected compared with normal corneas.52
As discussed earlier, the evidence to date also
points at significant allelic heterogeneity for FECD,
with two mutations described in COL8A2,23 in addition to solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) a sodium-coupled
borate transporter of the human plasma membrane
that is also associated with congenital hereditary
endothelial dystrophy type 2 and Harboyan syndrome (Table 2).53,54
Investigation of the mechanism for FECD associated with COL8A2 mutations has demonstrated
an abnormal intracellular accumulation of the mutant collagen VIII peptides as trimeric proteins.55
Disease-causing mutants in the SLC4A11 protein
may be divided into two classes on the basis of the

2013 Royal Australian and New Zealand College of Ophthalmologists

Corneal dystrophies and genetics

location and the subsequent effect on folding, with
those associated with late-onset FECD located
outside the lipid bilayer.56 SLC4A11 exists as a
dimer, and FECD mutants reduce the cell surface
processing efficiency of wild-type SLC4A11, which
is consistent with dominant inheritance of FECD.57
The locus for FECD2, previously mapped to chromosome 18q in a autosomal dominant FECD2 pedigree,
was probed with next-generation sequencing, and a
missense mutation was identified in the lipoxygenase homology domains 1 (LOXHD1) gene.58 This gene
was previously demonstrated to cause progressive
hearing loss. A further cohort of over 200 sporadic
FECD patients were sequenced, and a further 15
missense changes identified in this gene. It is predicted that the mutations identified would affect
proteinprotein interactions and also reside on the
surface of the protein, affecting the interface of the
protein. Analysis of the cellular expression demonstrated prominent cytoplasmic aggregates. An earlier
study had highlighted a significant association of
hearing disability in a cohort of 72 FECD patients
compared with a control population (odds ratio 1.97;
95% confidence interval 1.043.75).59
Mutations in the SLC4A11 gene are also associated with Harboyan syndrome: autosomal recessive
congenital corneal endothelial dystrophy and progressive perceptive deafness.60 SLC4A11 is located in
the fibrocytes underlying the stria vascularis in the
inner ear. SLC4A11 is essential for the generation of
the endocochlear potential, and loss of SLC4A11
leads to morphological changes in the fibrocytes and
deafness.61

EPITHELIAL RECURRENT EROSION DYSTROPHY

Recurrent corneal erosions spontaneous and iatrogenic remain a common problem in everyday ophthalmic practice. A number of isolated families have
been demonstrated to show autosomal dominant
inheritance of this phenomenon, although to date no
gene is identified. In IC3D, this entity is classified
as epithelial recurrent erosion dystrophy, with the
majority being category 4. The original pedigree
described by Franceschetti in 192862 has recently
been revisited, with further family members recruited and phenotyped.63 This family shows some
similarities to an autosomal dominant pedigree
we previously described, with an anterior membrane
dystrophy, and recurrent corneal erosions starting
from the age of 5 until about the age of 20.13 In this
family, candidate corneal genes and loci at that time
were excluded by linkage analysis. Both these dystrophies are category 3 dystrophies. Two further
autosomal dominant epithelial recurrent erosion
dystrophy have also been described, with exclusion
to known loci using haplotype analysis: the Smolan-

9
diensis variant64 and the Helsinglandica variant.65
Using the gene discovery technologies now available, it is likely that further gene identification will
be possible using these unique families, and any
identified gene variant may provide clues to the
wound-healing process in both health and disease.

GWAS
Another tool in the approach to identify genes
involved in complex disease is to use GWAS in casecontrol cohorts. These studies aim to identify SNPs
at which the allele frequency differs significantly
between cases and controls. The finding of such an
SNP then implies that a potentially causative variant
is located in linkage disequilibrium with that SNP
(i.e. usually inherited with the SNP due to physical
proximity and disinclination towards recombination). This technique was used successfully in the
identification of the TCF4 risk allele with FECD. A
drawback, however, is the requirement for large
populations of cases and controls. An alternative
approach is to look at the spectrum of relevant quantitative traits in a normal population in order to
determine which genetic variants SNPs are associated with a given trait. Recently, such GWAS have
probed the genetic determinants of central corneal
thickness, in particular as a determinant or risk factor
for the development of glaucoma,6668 with evidence
suggesting the role of collagen genes and a zinc
finger binding protein, zinc finger protein 469
(ZNF469), that causes autosomal recessive brittle
cornea syndrome.69 A GWAS has also highlighted
other genes including ZNF469 as associated with in
the pathogenesis of keratoconus,70 with heterozygous pathogenic changes detected in up to 46% of
individuals tested.71
Keratoconus and ectasias are not true corneal
dystrophies, but rather processes of bilateral noninflammatory progressive thinning of the cornea; a
recent review article covers this in greater detail.72
Keratoconus is mentioned in this discussion in part
because of the overlap with genes causative of other
corneal dystrophies (genetic heterogeneity and phenotypic heterogeneity; see Table 2) and the reported
co-occurrence of keratoconus with many different
corneal dystrophies.
The power of GWAS to help pinpoint the underlying genetic mechanisms in corneal disease and in
particular the evidence that central corneal thickness
is clearly genetically determined is one significant
finding in health and therefore in disease.
Meesmann corneal dystrophy is due to mutations
in either the keratin 12 or keratin 3 genes. Recent
work directed at the common founder mutation in
keratin 12, Arg135Thr, using allele-specific small
interfering RNA silencing shows promise in the

2013 Royal Australian and New Zealand College of Ophthalmologists

10

Vincent

future as a potential personalized medicine for Meesmann corneal dystrophy and potentially for other
ocular surface pathologies with dominant-negative
or gain-of-function disease causing mechanisms.73

CONCLUSION
Very few inherited corneal dystrophies remain
without any underlying molecular cause identified.
Although genes have been identified for many entities, for a number of these dystrophies only a small
number of cases remain genetically characterized, in
particular FECD and PPCD. The current tools of
next-generation sequencing, bioinformatics analysis
and genetic variation databases should lead the way
to more rapid identification of novel genetic mechanisms, particularly for those dystrophies for which
linkage has already been established. A greater
probing of the underlying functional mechanisms
and interactions of the mutant proteins is that each
dystrophy may in turn highlight and identify therapeutic targets. Marked phenotypic and allelic heterogeneity observed suggests that collectively, the genes
implicated are involved in collagen or extracellular matrix pathways, with complex but related
interactions.

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2013 Royal Australian and New Zealand College of Ophthalmologists