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Lens biology: development and human cataractogenesis Reviews

Lens biology
development and human cataractogenesis
Cataract, or opacification of the lens of the eye, is the commonest cause of visual impairment world-wide. It is
only treatable at present by surgical removal. Recent advances in our understanding of the genetics of human
cataract, in particular the inherited congenital form, together with the development of an array of animal models
have provided valuable new insights into normal vertebrate lens biology and the mechanisms that underlie
cataract formation. In this article, we review the current state of research in these areas and discuss thinking
regarding the relationship between the phenotypes observed and the underlying genotype in inherited cataract.
Peter J. Francis*
ataract, or opacification of all or part of the lens of the 9
the epithelial cells of the lens placode . Invagination of this p.j.francis@hgmp.mrc.
C eye, reduces optical performance, most commonly
manifested by decreased visual acuity, glare and decreased
area produces the lens pit, which closes over to form
the lens vesicle. A temporary connection with the surface
ac.uk
Vanita Berry§
contrast sensitivity. While age-related cataract is the ectoderm is retained (the lens stalk). vberry@hgmp.mrc.
commonest cause of visual impairment world-wide1, most Cells lining the posterior wall lose their nuclei and ac.uk
advances have been made in understanding the genetic rapidly elongate, obliterating the cavity of the vesicle to Anthony T. Moore‡
basis of its congenital counterpart. form primary lens fibres. Secondary lens fibres are subse- atm22@hermes.cam.
Congenital cataract is the commonest treatable cause of quently produced throughout life by division of anterior ac.uk
childhood blindness in Europe and the USA with a preva- lens epithelial cells in the equatorial zone of the lens and Shomi Bhattacharya¶
lence of 1.8 cases per 10 000 (Ref. 2). Presentation is most form lamellae, compacting more central fibres10. Mature lens smbcssb@ucl.ac.uk
usual in early infancy, with static or slowly progressive lens fibres do not divide and there is minimal turnover of their
opacities that are usually bilateral and symmetrical. The protein constituents. Points at which secondary lens fibres *Department of
level of irreversible visual compromise that arises without come into apposition result in lines of optical discontinu- Molecular Genetics,
appropriate management depends upon the position of the ity or ‘sutures’11. The lens is surrounded by a capsule of Institute of
opacity within the lens and the degree of opacification3. mesenchymal origin. Successful organogenesis results in a Ophthalmology,
University College
Inherited cataract accounts for around half of all con- transparent biconvex lens suspended in the eye by zonular
London, 11–43 Bath
genital cataract4 and is a recognized feature of almost 200 ligaments, between the aqueous humour and the vitreous
Street, London,
genetic diseases5, including galactosaemia, Nance–Horan body. Exchange of waste products and nutrients occurs UK EC1V 9EL; and
and Down syndromes. In most instances, however, with the aqueous humour across the semi-permeable lens Moorfields Eye Hospital,
cataract is inherited non-syndromically as an isolated capsule12. 162 City Road, London,
abnormality. In non-consanguinous populations, the Secondary lens fibre formation does not result in opti- UK EC1V 2PD.
majority of inherited cataract shows autosomal dominant cal homogeneity. Instead, concentric zones of varying §
Department of Molecular
inheritance. Many apparently sporadic congenital cataracts refractive index develop, whose interfaces can be clearly Genetics, Institute of
might also have a genetic basis4. delineated. The zones correspond to different developmen- Ophthalmology,
The first description of a family with inherited cataract tal stages, although controversy remains about their pre- University College
London, 11–43 Bath
was published by Nettleship and Ogilvie in 1906 (Ref. 6). cise nature. A nomenclature that best reflects the cataract
Street, London,
Later, Nettleship described a genealogically distinct family phenotypes observed, and one that has a biochemical and
UK EC1V 9EL.
with a similar phenotype. This family was re-investigated histological basis, proposes that the lens consists of two ‡
Consultant
in 1963, and the disease shown to co-segregate with the parts: the nucleus, which is the total lens at birth, comprising Ophthalmologist,
Duffy blood group locus7. This became the first human embryonic and fetal parts, and the cortex that is laid down Moorfields Eye Hospital,
autosomal disease to be genetically linked when in 1968, after birth13. 162 City Road, London,
the Duffy locus was assigned to chromosome 1 (Ref. 8). UK EV1V 2PD; and
Molecular and cell biology of lens development Addenbrooke’s Hospital,
Lens morphogenesis The lens forms through a temporally and spatially regu- Hills Road, Cambridge,
Studies of lens embryology and gene expression have lated pattern of differentiation, coordinated by several UK CB2 2QQ.

made important contributions to our current understand- growth factors, for example fibroblast growth factors Department of
Molecular Genetics,
ing of the developmental periods during which the lens is FGF1, -2, -3 and activin, and transcription factors such as
Institute of
susceptible to adverse influences, thus helping to explain PAX6, SIX3, SIX5 and PITX3. The roles of OPTX2 and Ophthalmology,
the observed spatial and temporal patterns of cataract. In retinoic acid in transcriptional regulation are less well University College
the human, lens organogenesis (Fig. 1) begins in the 4 mm established. In turn, the presence of the developing lens London, 11–43 Bath
embryo (fourth week of gestation) with thickening of appears to be crucial for the normal development of other Street, London,
the surface ectoderm overlying the optic vesicle to form ocular structures. UK EC1V 9EL.

0168-9525/99/$ – see front matter © 1999 Elsevier Science All rights reserved. PII: S0168-9525(99)01738-2 TIG May 1999, volume 15, No. 5 191
Reviews Lens biology: development and human cataractogenesis

role of PAX6 in later ocular development is not com-


FIGURE 1. Lens morphogenesis
pletely known. It appears to be is involved in the regu-
lation of lens crystallin expression both as an activator
(a) (b) and a repressor19. Indeed, mutations resulting in prema-
Lens placode ture truncation of the PAX6 protein have recently been
Surface ectoderm implicated in the development of human cataract.
Retinoic acid has also been implicated as a regulator of
crystallin expression20.
Optic vesicle
Other homeobox genes, PITX3 (expressed in lens pla-
code and forming lens pit)21, SIX3 (expressed in the optic
vesicle and anterior neural plate)2 and OPTX2 (expressed
in lens placode and optic vesicle), also appear to play
(c) (d) Lens important sequential roles in the induction of eye and lens
Cornea
stalk development. SIX5 is not expressed during eye develop-
Lens pit ment but in the mature lens where the dysfunction of its
protein product has been implicated in the development of
human cataract22.
Lens Lens cup
Transparency of the lens results from the highly
vesicle ordered arrangement of the macro-molecular components
of constituent cells and the regular arrangement of lens
fibres. Mature lens fibres are hexagonal in cross-section
(Fig. 2), and being devoid of nuclei and organelles to
(e)
Anterior pole reduce light scattering, are metabolically inactive. Protein
Cornea accounts for a third of the wet weight of the lens, nearly
Primary lens double that found in other tissues.
fibres
Lens cell physiology is entirely directed to the mainte-
nance of this architecture serving to minimize oxidative
Equator
stress (catalase, glutathione redox cycle and the mercap-
topuric pathway), and changes in hydration and elec-
trolyte imbalance. Metabolic activity is highest in the lens
epithelium, an elaborate system of gap junctions allowing
Posterior pole
communication with the metabolically inert cells deep
within the lens23.
Crystallins, the main cytoplasmic proteins, are a
heterogeneous group of highly stable, water soluble
molecules. Originally, crystallins were thought to be local-
ized in the lens to provide transparency. It is now clear
that many crystallins, found in exceedingly high concen-
trations in the lens, are encoded by a family of genes that
also specify metabolic enzymes and stress proteins found
(a, b) Lens morphogenesis begins with the thickening of surface ectoderm overlying the optic vesicle,
in other tissues. This multiple use of a distinct protein
which then (c) invaginates (lens pit) and (d) closes over to form the lens vesicle. (e) Cells lining the encoded by a single gene, termed ‘gene sharing’, seems
posterior wall elongate (primary lens fibres) to fill the lumen. Throughout life, proliferation of likely to be widespread in the lens, cornea and other
epithelial cells in the equatorial region produces secondary lens fibres that elongate to form lamellae ocular tissues24.
surrounding the embryonic nucleus. In humans, crystallins are categorized into a, b and g
subgroups. b- and g-crystallin are closely related globular
proteins whose two domain structure is distinguished by
The presence of transcripts of three subtypes of FGF in four, stable, torqued b-pleated sheets known as ‘greek key
the developing optic cup and vesicle suggests an important motifs’. These motifs enable crystallin molecules to associ-
role for these growth factors in normal lens development. ate to form highly compact oligomers whose light-scatter-
There is now evidence that lens fibre differentiation and ing properties are further reduced by the internalization of
subsequent survival is dependent upon their activity14. all hydrophobic residues25. The a-crystallin molecule does
PAX proteins are multifunctional transcription factors, not contain these motifs suggesting that it is not closely
critical for numerous developmental processes in animals. related to b- and g-crystallins26.
PAX6, which contains a paired domain/homeodomain is The structural framework of lens cells is composed of
essential for early eye determination15, the specification of cytoskeletal proteins typical of most mammalian cells.
ocular tissues and normal eye development in verte- However, secondary lens fibre elongation and compaction
brates16. Heterozygous mutations in PAX6 of vertebrates are accompanied by alterations in the expression of sev-
are associated with abnormalities, such as aniridia and eral components of the cytoskeletal architecture. In the
microphthalmia16. Homozygous PAX6 mutations are mature lens fibre cell, keratin and vimentin are not
lethal and are associated with severe brain defects and a expressed27. Instead, CP49 (phakinin) and CP115/CP95
complete absence of the eyes17. Furthermore, targeted (filensin) assemble to form a novel cytoskeletal structure
expression of the Drosophila PAX6 homologue, eyeless, referred to as the beaded filament. This structure differs
produces supernumerary eyes, suggesting that PAX6 is a from other intermediate filaments and appears to have the
key regulatory gene for eye morphogenesis18. The precise ability to interact with a crystallin.

192 TIG May 1999, volume 15, No. 5


Lens biology: development and human cataractogenesis Reviews

The role of a-crystallin, the most Nakano (nct) mouse which is due to a
abundant protein in the lens, is not
FIGURE 2. Lens transparency recessive mutation mapped to chro-
yet clear, but its function as a chaper- mosome 16. At present, no suitable
one protein has recently been linked candidate gene has been identified,
to the dynamics of mammalian though biochemically, defects in lens
cytoskeleton assembly because correct Na-K-ATPase enzyme activity are
folding of cytoskeletal proteins is suspected33.
28,29
dependent upon its presence . Almost 100 cataract mutants have
Maintenance of lens cell homeosta- now been engineered with abnormali-
sis is reliant upon the presence of an ties of development, immunity, growth
extensive array of membrane channels Cell membranes
and physiology (defects in membrane
comprising ‘thin’ and ‘gap’ junctions. transport, cytoskeleton and cytoplas-
Thin junctions regulate the highly mic proteins)34. It is reassuring that
selective transfer of water molecules the genetic defects so far identified
Connexin
across cell membranes. In the human (Table 1), mirror those implicated in
lens, the junction components are human cataract. For example, mouse
probably aggregates of the following g-crystallin35 and connexin36 gene mu-
proteins30: MP26 (major intrinsic pro- tations result in phenotypes not dis-
tein or MIP) and MP19 (also referred Connexon similar to their human counterpart.
to as MP18 and MP17), which show The data confirm the crucial role that
striking sequence homology with both studies of mouse models will play in
channel-forming integral protein and revealing human cataractogenic mech-
aquaporin proteins. Several different anisms. However, it will be known
conformations have been identified, only with hindsight whether many
each appearing to have specific gating more of these laboratory-induced
properties. strains will be found to parallel spon-
Gap junctions allow ions, second Extracelluar gap
taneously occurring mutations or
messengers and small metabolites to whether transgenic models will prove
be shared between cells. These inter- more informative.
cellular channels are formed from two Lens transparency is maintained not only by the
ordered packing of crystallin molecules but also
oligomeric membrane protein assem- Molecular genetics of human
by the regular arrangement of mature lens fibres,
blies, called connexons, which span
which are devoid of nuclei and hexagonal in
cataract
the plasma membranes of two adja- cross-section. An elaborate array of gap junctions Congenital cataract shows wide pheno-
cent cells to join in a narrow extra- allows intercellular communication. A gap typic variation reflecting its genetic
cellular ‘gap’ (Fig. 2). Connexons are junction is formed by the association of two heterogeneity. No agreed nomenclature
formed from connexins, a highly connexons across the extracellular space. exists for the different morphologies
related multigene family with at least observed in humans, though several
13 members31. Connexins 46 and 50 classifications have been proposed.
are found in the human lens. Considerable progress has Current literature recognizes the following phenotypes,
been made in our understanding of the complex molecular which are described in a fashion that combines both the
switches that control the formation and permeability of these location of the opacity within the lens as well as the
channels. Furthermore, analysis of the mechanisms of appearance: anterior polar, posterior polar, nuclear, lamellar
channel assembly has revealed the diversity of inter-connexin (zonular), coralliform (coral-like appearance), blue-dot
interactions and provided insights into the selectivity of (cerulean), cortical, pulverulent (opacities have a ‘pulverized’
their gating behaviour32.

Mouse models of cataractogenesis TABLE 1. Mouse mutants where genetic defect is knowna
Animal models are valuable tools with which to study
human disease. The detailed information available regarding Mouse Mutant Cataract phenotype Genetic defect Human synteny
chromosome
eye development in the mouse and the fact that cataracts
are easily identified in this animal, make it an ideal candi- 1 Cat2 t Total opacity with g-E crystallin g-E crystallin
date for the study of cataractogenesis. Furthermore, the microphthalmia (2q33–35)
extensive regions of synteny that exist between the human Cat2 nop
Nuclear opacity g-B crystallin g-B crystallin
(2q33–35)
and mouse genomes facilitate comparative mapping and Cat2 ENU-436 Diffuse nuclear opacity g-A crystallin g-A crystallin
enable identification of novel candidate loci for human (2q33–35)
cataract. Studies of the molecular and developmental Cat2 elo Eye lens obsolescence g-E crystallin g-E crystallin
pathobiology of mouse cataract models are also likely to (microphakia) (2q33–35)
3 No2 Nuclear opacity Connexin 50 Connexin 50 (1q21–25)
reveal mechanisms underlying human cataract development. 5 Philly (Phil ) Nuclear opacity bB2-crystallin b-B2 crystallin (22q)
While spontaneous mouse cataract mutants are recog- 7 To3 Total opacity LIM2, MP10 LIM2 (19q13.4)
nized, new strains can be developed by irradiation (X-ray, 10 Cat Fr Progressive lens fibre Major intrinsic MIP (12q)
degeneration protein (MIP)
g-ray) or by the use of chemical agents such as ethylni- Cat lop Opacity beginning
trosourea. In most instances, dominant mutations are gen- anteriorly
erated, a corollary of the inheritance pattern observed in 19 ak Aphakia PITX3 PITX3 (10q25)
humans and suggestive that the mutated genes encode a
Reviewed in Refs 33–36.
proteins with structural roles. A notable exception is the

TIG May 1999, volume 15, No. 5 193


Reviews Lens biology: development and human cataractogenesis

FIGURE 3. Human inherited cataracts

Lens
opacity

Normal lens with oblique illumination (right) Sclera Lower lid Lens Iris Lens Corneal reflection

Nuclear cataract with retroillumination view (right) Iris Lens Lens Cataract

Posterior polar cataract with retroillumination (right) Iris Lens Sclera Lens Reflection

Nuclear and lamellar cataract with oblique illumination (right) Iris Lens Lower lid Lens Cataract

Large pulverulent cataract with oblique illumination (right) Iris Lens Lens

Human inherited cataracts exhibit considerable variations in morphology and distribution of opacification. The photographs on the first row show a normal lens
without cataracts. Below are four examples of lens cataracts with retro- or oblique illumination images to the right-hand side. Retrollumination uses diffuse light
reflected from the blanched retina to ‘silhouette’ the cataract, while oblique illumination makes use of a fine slit beam of light directed obliquely through the lens.
A schematic of each view is included.

dust-like appearance) and total37. It is increasingly appar- Connexin genes


ent that this nomenclature parallels quite accurately the The report of the co-segregation of a family with pulveru-
underlying genotype. Examples are shown in Fig. 3. lent cataract with the Duffy blood group locus on human
Independent loci for human non-syndromic dominant chromosome 1 in 1963 (Refs 7, 8) has been described
congenital cataract have been mapped by linkage analysis above. The Duffy (FY) locus has now been refined to
to at least eight different chromosomes38. Furthermore, 1q22–23, and lies close to the gap junction a-8 (GJA8)
the finding of cytogenetic abnormalities in some patients gene at 1q21.1. GJA8 encodes connexin protein 50, pri-
with congenital cataract has identified putative loci on marily and abundantly expressed in human lens39 making
2p22.3, 14q24 and Xp. Also, improved understanding of GJA8 a strong candidate for pulverulent cataract. The
lens development, lens physiology and mouse cataract missense mutation (C to T transition at nucleotide 262)
models has generated a large number of candidate genes underlying the cataract in this family results in the substi-
associated with cataracts in humans. We discuss below tution of serine for proline at codon 88, which lies within
the nature of the mutations identified so far, and this the phylogenetically conserved second transmembrane
information is summarized in Table 2. region of the protein38. Further evidence to implicate this

194 TIG May 1999, volume 15, No. 5


Lens biology: development and human cataractogenesis Reviews

gene in human cataractogenesis has been provided by


TABLE 2. Identified mutations implicated in human congenital
the identification of another mutation in an ethnically
unrelated family (Pakistani) with pulverulent cataract cataract
(V. Berry, unpublished), predicted to disrupt connexon- Locus Gene Protein Mutation Phenotype Ref.
connexon interactions by altering the electrical charge
distribution in the extracellular loop of the protein. 1q21–25 GJA8 Connexin 50 Missense Pulverulent 38
A mutation in the gene coding for another gap junction 2q33–35 CRYG g-Crystallin Pseudogene activation Pulverulent 44
Coppock-like
protein, connexin 46, has recently been shown to underlie 10q24–25 PITX3 Pitx3 Missense Total 21
pulverulent cataract development in two families linked to 13q11–12 CX46 Connexin 46 Missense Pulverulent 41
13q (Ref. 40). In the first family, an A to G transition at 21q22.3 CRYAA a-Crystallin Missense Variable 46
nucleotide 188 results in the non-conservative substitution 22q CRYBB2 b-Crystallin Chain termination Cerulean (blue-dot) 45
of serine for asparagine at codon 63 (Ref. 41). This mis-
sense mutation lies in the first extracellular loop of the enolase deficiency shows no evidence of cataract. Linkage
protein, believed to mediate the intermembrane coupling to the 1p36 locus has also been shown in a family with
of connexon hemi-channels42. In the second family, inser- posterior polar cataract48. This suggests either that two
tion of a cytosine after nucleotide 1137 is predicted to genes lie within this locus or, more interestingly, that dis-
cause a frame shift immediately after codon 379. This tinct mutations within a single gene have resulted in the
results in the mis-translation of the final 56 amino acids different phenotypes observed. While the chromosomal
and the addition of 31 amino acids to the C-terminus of location of many of the other crystallin genes is now known,
the mutant protein before an in-frame translation stop no mutations causing cataract have yet been identified.
codon is detected41.
Transcription factors
Crystallin genes The identification of a mutation in the human gene PITX3
The g-crystallin gene cluster located in region 2q33–35 in a family with total cataract is the first to implicate a
consists of genes g-A, -B, -C, -D, -E, -F and a gene frag- developmental regulator gene with congenital cataract.
ment g-G. Only g-B and g-D encode abundant proteins PITX3 is a member of the homeobox gene family RIEG/PITX
while g-E and g-F are pseudogenes by virtue of in-frame and has been localized to chromosome 10q24–25. A G to
stop codons (the g-F lacks a promoter as well). The A transition was identified that results in the substitution
Coppock-like cataract (pulverulent) was mapped to chro- of serine for asparagine at codon 13. The mutation is not
mosome 2q33–35 close to the g-D and g-E genes43 and a within the crucial homeodomain of the protein but does
mutation identified near the g-E gene TATA box. The occur in a highly conserved position and is purported to
result is an order of magnitude increase in promoter activ- result in the modulation of a DNA-binding site or inhibition
ity raising the level of expression of this gene to 30% of of protein–protein complex formation21.
that of the g-D gene. The predicted protein product is a
6 kDa N-terminal g-crystallin fragment, the over expres- Genotype–phenotype considerations
sion of which is hypothesized as the cause of the cataract44. Development and growth of the lens throughout life seem
The activation of a pseudogene in this way remains a to rely upon the sequential time-limited expression of a
unique pathogenic mutational mechanism. number of genes. The spatial and temporal patterns of
A form of congenital cerulean cataract has been cataract observed are, therefore, likely to be consequent
mapped to a region of chromosome 22q that contains upon the expression of a mutant form of one of these
three b-crystallin genes45 and a missense mutation identi- genes. So far, consistent with this view, no single gene has
fied in the crystallin bB2 gene. This finding is consistent been implicated in two distinct patterns of cataract, though
with the fact that the bB2 protein is the only crystallin that several genes, for example, the genes encoding connexins
is abundant in the adult lens fibre. The nucleotide change 46 and 50 are observed to produce the same phenotype.
in the first position of codon 155 creates a stop codon that While it seems that different mutations in the same gene
truncates the protein by 51 residues. Significantly, linkage would cause cataracts of the same general pattern, the
to this and the 17q24 loci have been excluded in other occurrence of posterior polar and pulverulent zonular
families with cerulean cataract confirming that a further nuclear cataracts both mapping to 1p36 and the highly
gene(s) remains to be identified in this form of cataract. variable morphologies of cataracts within some families
More recently, a missense mutation in the crystallin aA suggest that even the same mutation in a single gene can
gene has been identified46 in a family described as having cause a variable phenotype.
congenital zonular nuclear opacities. The nucleotide tran- The manner by which mutations in lens genes result in
sition results in the substitution of an arginine at position 116 cataract formation has yet to be established. Dysfunction
for a more negatively charged sulfhydryl-group-forming of any element essential for the maintenance of trans-
cysteine. It is hypothesized that this change increases a-crys- parency to visible light could result in opacification. With
tallin aggregation or interferes with chaperone activities. current evidence, it is tempting to speculate that this may
A large Danish family with nuclear cataract has been occur in three ways. A mutant protein for example a
assigned by linkage studies to the interval 1pter–1p36, crystallin, may lose its optical properties or fail to interact
within which lies the gene ENO1 (Ref. 47). This gene has appropriately with its intracellular environment. The
been considered a candidate because, by the process of failure of mutant proteins such as cytoskeletal proteins,
‘gene sharing’ (described above), it encodes not only red to facilitate crystallin packing may result in loss of optical
cell enolase 1 but also t-crystallin. However, despite its homogeneity. Disturbances in transmembrane signal
widespread expression within the lenses of vertebrate transduction, for example due to mutated connexin
species, t-crystallin is not expressed in the human lens. proteins, may result in disturbances of cell homeostasis,
Indeed, the only family described with hereditary red cell the accumulation of abnormal precipitates or frank

TIG May 1999, volume 15, No. 5 195


Reviews Lens biology: development and human cataractogenesis

disruption of cell architecture. It is possible to envisage Mutations of the TIGR gene49 were first identified in fam-
how such mutations may result in some of the patterns ilies with juvenile-onset glaucoma but were subsequently
of cataract observed. How polar cataracts form and found to play a role in the pathogenesis of adult-onset
why opacification may in some cases progress, is less glaucoma. Similarly, mutations in the ABCR transporter
well understood. gene50 not only cause a juvenile-onset macular dystrophy
but have also been implicated in the pathogenesis of early-
Conclusions and future perspectives onset macular degeneration. It is likely therefore that
Congenital cataract is clinically and genetically heterogen- genes implicated in inherited congenital cataract also play
eous. To date, 18 independent loci and mutations in 6 a role in determining susceptibility to age-related cataract.
genes have been identified. Advances in microsatellite- It is estimated that despite surgical removal of the lens
based linkage techniques of suitable human pedigrees sug- and subsequent optical correction, a third of patients with
gest that the positional-candidate gene approach will con- congenital cataract will remain legally blind51. The
tinue to provide an increasingly efficient and powerful removal of adult cataract with intra-ocular lens insertion,
methodology for the identification of genes causing though not without risk, carries a much better prognosis
human cataracts. and vision is often restored to pre-morbid levels. In the
Further study of mouse models and the advancement of developing world however, health provision is often inad-
genome mapping projects will undoubtedly yield more equate to meet the eye-care needs of the population. Even
candidate genes. Clearly, the voyage towards a full under- in developed countries, patients incur significant morbid-
standing of the genotype–phenotype relationship has only ity from cataracts before surgery. The end point of research
just begun. into the molecular genetics of cataract must therefore be
The identification of the genetic mutations causing con- the introduction of novel medical therapies, possibly involv-
genital cataract will not only improve our understanding ing gene manipulation, to prevent or treat the condition
of the pathogenesis of infantile cataract and the develop- which remains the commonest cause of visual disability in
mental biology of the lens but also adult-onset cataract. humans.

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