Understanding the molecular mechanisms underlying cataract development


A greater understanding of lens embryology and the phenotype/genotype correlation of cataracts should help guide future therapeutic approaches.

Scientist stue

Cataract is the most common cause of blindness worldwide1 and a very significant cause of visual impairment in infants and children. Congenital cataracts are seen in 10–60/100,000 births in the UK and 50–150/100,000 births in developing countries.2

Improving our understanding of the underlying molecular mechanisms behind cataracts will positively impact clinical care, triggering the development of non-surgical treatment strategies. For example, the identification of genetic variants causing congenital cataract has not only improved our understanding of the pathogenesis of infantile cataract, the most frequent treatable cause of blindness in childhood, but also its more common counterpart, adult-onset cataract.

This may lead to new strategies for preventing cataracts or mitigating the progression of early lens opacity, thus reducing the huge global demand for surgery.

Lens development

The ocular lens provides a unique model for understanding the inductive interaction of various embryonic tissues, as well as cell differentiation, signalling, proliferation, physiology, biochemistry, longevity and organelle degradation. The structure is surrounded by a thick capsule and filled with elongated lens epithelial cells (LECs) that have differentiated into lens fibre cells.

The lens is the only organ that continually evolves and increases in size without replacing any cell in its system. Regardless, it performs its role to refract light onto the retina until mutation or the effects of ageing, the environment or intrauterine infections compromise its transparency and optical function. Such insults cause changes to the biomolecules and trigger homeostatic imbalance in the lens, leading to protein aggregation and cataracts, and thus increasing light scatter to affect refraction and cause loss of vision.

Lens development is a result of a series of inductive events during eye morphogenesis. The eye begins to develop during gastrulation at the beginning of week 4 (day 22, Carnegie stage 9). A single eye field (eye primordium) arises in the middle of the anterior neural plate (diencephalon region of the developing brain), which separates into two optic vesicles and induces the overlying surface ectoderm to form the lens placode (lens primordium) by day 28 (Carnegie stages 12–13).

During this stage, a series of inductive interactions begin to shape the eye, driven by signalling molecules such as bone morphogenetic proteins and fibroblastic growth factor 2, as well as by eye field transcription factors including PAX6, RAX, SIX3 and LHX2.3–5 The lens placode invaginates to form the cup-shaped lens pit, which makes a complete circle of cells and separates from the surface ectoderm to develop into the lens vesicle. By the end of week 4 (Carnegie stages 10–13), the cells from the posterior vesicle start to elongate towards the anterior epithelial cell layer to become the primary lens fibres that fill the lens vesicle and later become the embryonic nucleus of the mature lens.

The portion of the optic vesicle that faced the lens placode gives rise to the retina. The retina, in turn, provides oxygen and inductive signals that regulate the growth and apical-posterior axis of the lens, and this tissue integration continues to enable the functional optimisation of eye function with the establishment of emmetropia.

In the early optic cup stage, the lens vesicle releases signals that induce the overlying surface ectoderm to differentiate into the corneal epithelium. After the lens vesicle has closed (weeks 4–5; Carnegie stage 15), secondary fibre cells add to the growing lens as the foetal nucleus starts to form in weeks 6–7 (Carnegie stages 16-19), derived from the epithelial cells located at the equator of the developing lens.

Around week 8 (Carnegie stage 20), the Y-shaped suture appears at the anterior and posterior poles of the embryonic nucleus of the lens, as the terminal ends of the secondary lens fibres abut each other. During this process of terminal differentiation, fibre cells degenerate their nuclei and other cell organelles such as ribosomes and mitochondria, the Golgi apparatus and the endoplasmic reticulum to minimise light scattering and optimise the optical function of the tissue.

Congenital cataracts

Childhood cataract may occur in isolation associated with other ocular abnormalities, such as anterior segment mesenchymal dysgenesis due to variants in transcription/development factors, or be part of multisystem genetic disorders. Nearly half of congenital cataracts are characterised as inherited and they are a clinical feature of almost 200 syndromic genetic diseases.6 Cataract was the first autosomal disease to be genetically mapped in humans following its identification at the start of the 20th century.7,8 Since then, congenital cataract has been shown to be associated with considerable genetic and phenotypic heterogeneity.9–11

Mode of inheritance and phenotype/genotype correlation

Most (57.5%) inherited cataracts are autosomal dominant (AD) with complete penetrance but variable expression; autosomal recessive (AR; 21.4%) and X-linked (XL; 6.2%) inheritance are less frequent.12 There are several distinct phenotypes of congenital cataract (Figure 1A), defined mainly by the timing, position (embryonic, foetal or cortical) and appearance (nuclear, cortical, complete, blue-dot, anterior polar, posterior polar, pulverulent, lamellar, coralliform, posterior nuclear or polymorphic) of the opacification during lens development (Figure 1B).13,14

To date, 1,460 novel and recurrent disease-causing sequence variants have been identified,12 with a well-defined distinct phenotype observed in 823. Nevertheless, it is important to remember that phenotypic variability is seen within families with the same mutation;10 conversely, different variants in different genes can present with the same phenotype.10,15 This emphasises the multifactorial nature of cataract formation and the contribution of non-genetic environmental and lifestyle factors.15

Graph showing cataract phenotypes and photos showing inherited cataract phenotypes

Molecular genetics of inherited cataract

To date, 356 genes have been found to be associated with syndromic and non-syndromic cataract and nearly 50 disease-causing genes have been identified to be associated with isolated cataract (Figure 2). Disease-causing variants have been identified in genes encoding many different proteins and can be categorised into different groups according to their biological role in the lens, as follows:

  • Intracellular lens proteins (the crystallins);
  • Membrane proteins, which are the water channel proteins (aquaporins) that regulate water transport, gap junction proteins (connexins) and lens integral membrane protein (LIM2);
  • Transcription factors including PAX6, SOX, PITX3, FOXE3 and MAFA;
  • Cytoskeletal proteins including BFSP1 (filensin), BFSP2 (CP49; phakinin) and VIM (vimentin), which stabilise the plasma membrane and the fibre cells themselves; and
  • Gene products with special roles in the lens, including EPHA2, FYCO1 and TDRD7, and for lipid metabolism (LSS)12 (Figure 2).

Recent advances in molecular genetics, particularly next-generation sequencing, has improved molecular diagnosis in the clinic.16

graph showing variants in highly expressed genes in the lens

Intracellular lens proteins


Crystallins(α, β and γ) account for nearly 90% of all lens proteins and are essential for the lens’ optical properties and function and for its remarkable resilience, sustaining optical function over centuries in some animals17and maintaining transparency.18,19 Nearly 23% of congenital cataracts are due to mutations in crystallin genes.

Alpha-crystallins (αA-crystallin and αB-crystallin) are members of the small heat shock protein family, which are molecular chaperones protecting lens proteins and enzymes from aggregation, which could otherwise lead to lens opacification, and assisting in protein assembly.20 CRYAA is primarily expressed in the lens, while CRYAB is expressed in the lens epithelial cells and also in the retina, skeletal muscle, heart, kidney and brain.21,22

The βγ-crystallins comprise four homologous Greek key motifs organised into two domains.23 The β-crystallin family comprises three acidic (A) and three basic (B) forms.

γ-Crystallins are encoded by the γ-gene cluster, which encompasses genes CRYGA to CRYGB.24,25 Fewer sequence variants have been identified in γA and γB than γC and γD, although, interestingly, most of the variants in the CRYGC and CRYGD genes cause AD nuclear and coralliform cataract phenotypes. There is a single γS-crystallin gene (CRYGS) whose variants are linked to AD cataract but have a broad phenotypic spectrum.

Membrane proteins


The lens is an avascular, ever-growing organ; to maintain its life-long transparency and nourishment, especially in the mature fibre cells of the lens core, it has developed a sophisticated cell-to-cell communication network via gap junction proteins called connexins. These 20 transmembrane proteins, expressed in various tissues,26,27 allow the flow of ions, second messengers and metabolites between lens fibre cells and are made up of three connexin isoforms: GJA1 (Cx43), GJA3 (Cx46) and GJA8 (Cx50).

So far, 162 pathogenic variants have been found in connexin genes: 63 in GJA3, with various associated lens phenotypes including pulverulent, nuclear, lamellar, coralliform and total, and 99 in GJA8, associated not only with inherited cataract but also age-related cataract and other eye anomalies including microcornea, microphthalmia and corneal opacification.28 GJA1 is expressed only in the lens epithelial cells during early stages of lens development and is not associated with lens pathology.29,30

MIP26 (AQP0)

This is a member of the ubiquitous family of water channel proteins called aquaporins that allow rapid movements of water across cell membranes. MIP is highly expressed in terminally differentiated lens fibre, comprising nearly half of the total lens fibre cell membrane proteins.31

Berry and colleagues32,33 identified two AD variants (G134E and T138R) leading to polymorphic and lamellar cataract. So far, 37 heterozygous variants have been found in MIP, all causing AD cataract.

LIM2 (MP19)

This is another lens-specific integral membrane protein, found at the junctions of lens fibre cells, where it may contribute to cell junction organisation. It acts as a receptor for calmodulin and may play an important role in both lens development and cataractogenesis. Mutations in LIM2 have been associated with AR cataracts and age-related cataracts.34,35

Transcription factors

PAX6, FOXE3, HSF4, MAF and PITX3 are examples of transcription factors (TFs) that play an important role in lens development. PAX6, the paired-box protein, is a key player in vertebrate eye development and plays a key role in the regulation of lens-specific crystallins.36

FOXE3 is a forkhead-box TF required for morphogenesis and differentiation of the anterior segment of the eye. Disease-causing variants in this gene cause anterior segment mesenchymal dysgenesis and congenital cataracts. Nearly 21 homozygous and heterozygous variants have been reported, displaying severe developmental eye anomalies including cataract.

Another important gene is PITX3, a member of the REIG/PITX family of homeobox TFs.37 To date, 29 variants in PITX3 have been identified (including a hot spot in exon 4, c.640_656dup17bp) to cause mainly posterior cataracts and anterior segment dysgenesis in different ethnicities.38

Cytoskeletal proteins

The cytoskeleton of a cell comprises microfilaments, microtubules and intermediate filaments. In the lens, beaded filaments, a type of intermediate filament that is comprised of the proteins BFSP1 (filensin) and BFSP2 (CP49; phakinin), are expressed.39 Several variants in BFSP2 lead to sutural opacities and nuclear cataract in association with BFSP1 variants.

Nance-Horan syndrome (NHS) is also associated with abnormalities in the lens cytoskeleton and epithelial cell junctions. A total of 58 sequence variants in the gene underlying the XL-dominant NHS have been identified. Affected men have dense nuclear cataracts and frequently microcornea, whereas heterozygous women show sutural cataracts with microcornea, craniofacial dysmorphism, nystagmus, strabismus and dental anomalies.40,41

Cataract therapy and future direction

The timing of the appearance of cataract, either during infancy or at other life stages, depends on whether it is due to a harmful sequence variant or primarily due to accumulated biomolecular damage.15 Both can be described as accumulated cataractogenic load.

Effective therapeutic approaches have yet to be established for preventing or mitigating the cataract process. However, a therapeutic approach to treat cataracts by stabilising alpha-crystallin has been suggested42 and several studies have identified compounds that can reverse light scattering caused by protein aggregates, including the small molecule ‘compound 29’ (25 hydroxy-cholesterol), which binds to alpha-crystallin.

Lanosterol treatment has been shown to reverse crystallin aggregation in vitro43,44 although recent studies have cast doubt on the efficacy of the identified oxysterols lanosterol and 25 hydroxy-cholesterol to treat cataract.45 Genetic evidence clearly shows that deficiencies in cholesterol and lipid metabolism are linked to cataract, so the debate concerning statin use and cataract continues.46,47

Lens regeneration from endogenous stem cells has been developed to treat cataract: cataract lenses have been removed from mammals and human infants while preserving the lens capsule and LECs.42 In cases of inherited cataract, this method deploys further gene-editing using CRISPR/Cas9 technology in order to rectify the genetic variant in the regenerated lens.

Small-molecule therapy, using eye drops for example, seems to remain the most pragmatic solution in developing parts of the world, where immediacy and cost effectiveness is key. The search for small-molecule inhibitors has been ongoing with promising effects obtained with molecules such as pantethine, rosmarinic acid, polyherbal preparations and multi-functional antioxidants. Those that have shown the most promise have met the challenge of reducing cataractogenic load and this is therefore an important mechanistic focus for future work.48,49

The more invasive and time-consuming stem cell therapy approaches are apt in cases where gene editing is the only option to correct the mutant gene, e.g., inherited cataracts. Identification of genetic variants causing congenital cataract and elucidation of their impact on the lens is of vital importance to develop new therapies for cataracts.47


Vanita Berry, MSc, PhD
E: v.berry@ucl.ac.uk
Dr Vanita Berry is a senior research fellow at UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom.

Roy A. Quinlan, BSc, PhD
E: r.a.quinlan@durham.ac.uk
Prof. Roy Quinlan is professor emeritus at University of Durham, United Kingdom.

Michel Michaelides, BSc, MB, BS, MD(Red), FRCOphth
E: michel.michaelides@ucl.ac.uk
Prof. Michel Michaelides is professor at UCL Institute of Ophthalmology and Moorfields Eye Hospital, London.

For this work, Prof. Berry and Prof. Michaelides were supported by grants from Rosetree Trust (A2223), the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology (BRC-D-CON 546795), Moorfields Eye Hospital Special Trustees and Moorfields Eye Charity.


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