The eye starts developing on the 22nd day of gestation.¹ Shallow grooves first form on the opposite sides of the forebrain, eventually developing into outpockets called optic vesicles.¹ The vesicle comes into contact with the surface ectoderm and induces the differentiation of ectodermal cells into the lens placode.¹ The optic vesicle then invaginates and forms the optic cup and stalk.¹ The lens placodes invaginate as well to form the lens vesicles on both sides.¹ By the 5th week, the lens vesicle loses contact with the surface ectoderm and is located in the front part of the optic cup (Fig. 1.1).¹,²

Within the lens vesicle, the anterior cells give rise to a sheet of cuboidal epithelial cells.¹ The posterior vesicle cells elongate to reach the anterior wall by the end of week 7.¹ These long cells form the primary lens fibers filled with lens-specific proteins such as crystallins.¹,³

New secondary fibers are continuously added from the germinative zone—the section of epithelium just above the equator.⁴ Proliferation occurs rapidly here, with daughter cells migrating below the equator where they differentiate and elongate into secondary fiber cells.⁴ These new crescent-shaped cells organize in concentric circles over older cells while synthesizing crystallins.⁴ As these secondary fiber cells migrate through successive zones, they develop membrane undulations and eventually lose their cellular organelles to become compacted containers of protein solution.⁴ Eventually, the mature secondary fiber cells overlap in specific arc segments known as sutures.⁴ At birth, the suture pattern consists of three branches shaped as a Y.⁴ As the lens grows, the sutures become more complex, eventually forming six, nine, and then twelve branch sutures.⁴ The mature lens consists of an ordered organization of epithelial and fiber cells, with peripheral fiber cells meeting at the sutures.⁵

Lens differentiation is regulated by many transcription factors. Fibroblast growth factor (FGF) induces cell proliferation in low doses, whereas it induces cell migration and fiber cell differentiation at higher doses.⁶ Thus, the polarity of the lens may be due to the varying concentrations of FGF in the ocular media, with more FGF found in the vitreous than the aqueous.⁶ Bone morphogenetic protein (BMP) has also been shown to interact with FGF during early lens induction.⁶ For proper lens induction to occur, the canonical Wnt/β-catenin pathway must be down-regulated, while the antagonistic noncanonical Wnt pathway must be up-regulated.⁶ The Wnt/β-catenin pathway has also been shown to play a role in beta crys-tallin production.⁶ Finally, paired box 6 (PAX6) is crucial for the formation of the lens placode and the expression of crystallin genes.⁷ Crystallins are essential components of the lens, and mutations in crystallin genes account for many of the inherited nonsyndromic congenital cataracts.

α-Crystallins constitute approximately 35% of the lens.¹² They are small heat shock proteins that contribute to the refractive power of the lens, and act as a molecular chaperone.¹² Specifically, α-crystallins bind unfolded and denatured proteins in the lens to prevent aggregation.¹² Aggregated proteins will interfere with the refractive properties of the lens, leading to the formation of cataracts.¹²

Two types of α-crystallins exist in the lens: αA-crystallins and αB-crystallins. The αA-crystallin gene (CRYAA) is on chromosome 21 and encodes a 173 amino acid protein.¹² The αB-crystallin gene (CRYAB) is found on chromosome 11 and encodes a 175 amino acid protein.¹² The two α-crystallins share a 57% homology.¹² αA-crystallin is expressed solely in the lens while αB-crystallin is expressed systemically. The ratio of αA-crystallin to αB-crystallin in the lens is 3:1.¹²

Although α-crystallins are generally stable enough to tolerate many substitutions in its primary structure, certain mutations have been implicated in the formation of congenital cataracts.¹² These mutations alter the tertiary and quaternary structure of the protein, impinging on its ability to bind substrate proteins.¹⁰ Abnormal oligomerization of mutated α-crystallins have been found in congenital cataracts.¹⁰ These changes decrease the stability of the protein and reduce its chaperone ability.¹⁰ Mutations have also affected posttranslational modifications that lead to misfolded proteins that form aggregates and scatter light.¹³

An amino acid substitution mutation in the CRYAB gene leads to congenital cataracts but also systemic manifestations, since αB-crystallin is expressed ubiquitously.¹⁴ An A>G transition at nucleotide 3787 in the genomic sequence translates to the replacement of arginine at position 120 by glycine.¹⁴ The p.R120G mutation causes desmin-related myopathy, which is an autosomal dominant disease characterized by muscle weakness, cardiomyopathy, and congenital cataracts.¹⁴ Muscle biopsies show aggregates of desmin possibly due to altered interactions between desmin and the mutated αB-crystallin.¹⁴

A deletion in exon 3 (450delA) of the CRYAB gene leads to a frameshift mutation that manifests clinically as an isolated congenital cataract, inherited in an autosomal dominant pattern.¹³ The cataracts are described as bilateral posterior polar.¹³ Because the opacity is in the back of the lens and thus close to the optical center of the eye, visual acuity is severely affected.¹³ The opacity was either present at birth or developed within the first few months after birth but did not progress to any other parts of the lens.¹³

β-Crystallins are the most abundant water-soluble proteins in the lens, and their specific, closely packed arrangements play an important role in maintaining lens transparency.⁹ β- and γ-crystallins are very similar in structure. They both have two domains connected by an 8-10-amino acid peptide.¹¹ Each domain is composed of an identical polypeptide chain fold in a Greek key motif: a β-sandwich of two antiparallel β-sheets. Normally, βA3- and βB2-crystallins associate reversibly into homo- or heterodimers.¹¹ These dimers may either dissociate into monomers or further associate into multimeric complexes.¹¹ It is thought that the multimeric complexes are essential in maintaining lens transparency.¹¹ Mutations that disrupt the protein structure or change its ability to associate can cause nonspecific aggregates of these crystallins that precipitate cataract formation.

Padma et al. described a family with isolated congenital cataracts due to a mutation in the CRYBA1 gene that encodes βA3/A1-crystallin.¹⁵ Like most isolated congenital cataracts, it is inherited in an autosomal dominant fashion.¹⁵ All affected members exhibited both zonular and sutural cataracts.¹⁵ The fetal and embryonic nuclei in the zonular cataract were clear, while the sutural cataract involved an anterior erect Y-shape and a posterior inverted Y-shape.¹⁵

A chain termination mutation in the CRYBB2 gene that encodes for the β-2-crystallin protein has been implicated in a cerulean-type cataract.¹⁶,¹⁷ The cataracts manifest as blue flakes and spoke-like central opacities with only mild reductions in visual acuity.¹⁶

An autosomal recessive mutation in the CRYBB3 gene has been shown to cause a nuclear cataract with cortical riders.⁹ While crystallin-causing cataracts often follow an autosomal dominant inheritance pattern due to the structural function of the proteins, this autosomal recessive inheritance suggests that βB3-crystallin may play a role beyond that of structure, such as an enzyme or developmental protein.⁹

The γ-crystallins are part of the βγ-crystallin superfamily and like the β-crystallins, they form a Greek key motif with four β-sheets. It is thought that the γ-crystallins also contribute to the maintenance of lens transparency in a similar way to that of the β-crystallins. The γ-crystallins gene cluster, (CRYGA-F) is located in the loci 2q33-35.¹⁸ Mutations that cause cataracts have been identified mainly in the CRYGC and CRYGD genes, which also happen to the most expressed γ-crystallin genes in humans.¹⁸ The γS-crystallin gene, formerly known as βS-crystallin, is distinct from other γ-crystallins.¹⁹ γS-crystallin is found on chromosome 3, and the protein is structurally similar to the other γ-crystallins except in that it has an additional α-helix between the third and fourth β-sheets.¹¹

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