β-crystallins are the most abundant water-soluble structural proteins in the lens, making up approximately 35 % of the total protein. They are mainly expressed in lens fiber cells, with the highest level in cortical fiber cells [61]. β-crystallins have been shown to consist of seven subunits (βB1, βB2, βB3, βA1, βA2, βA3, and βA4) that are encoded by six CRYB genes; of these, both βA1 and βA3 are encoded by the same gene called CRYAB1.

A dozen mutation sites in β-crystallins have been identified to be associated with hereditary cataracts, most commonly seen in βB2-crystallins (Table 4.1) [16–30, 62, 63]. Mutations in β-crystallin result in diverse cataract phenotypes. An identical mutation may produce vastly different phenotypes among different families, or different degrees of the same phenotype within one family. For example, we found that in a family in South China, 22 family members were diagnosed as membranous cataract due to W151C mutation in exon 6 of the CRYBB2 gene (Fig. 4.2a). The same mutation was also reported in an Indian family, but its associated phenotype was nuclear cataract, indicating that an identical mutation might have diverse clinical phenotypes among different ethnic groups [27, 30]. In addition, even in this single Chinese family, the severity of membranous cataract also varied. The lens opacities were progressive with increasing age, accompanied by lens dislocation and membrane permeability changes, and the opacified cortex was gradually dissolved and absorbed (Fig. 4.2b) [30]. The mechanism of cataract development due to mutation in β-crystallin is that the amino acid substitution caused by the mutation leads to structural changes of proteins, resulting in an increase in hydrophobicity and a decrease in solubility and consequently protein aggregates and lens opacification [63].

γ-crystallins, accounting for about 25 % of the total protein of the lens, are highly stable monomeric proteins and are encoded by seven distinct genes. The genes encoding γA- to F-crystallins are all located on chromosome 2 with highly similar sequences, while the gene encoding γS-crystallins is found on chromosome 3. γ-crystallins, expressed specifically in lens fiber cells, are synthesized at the terminal stage of fiber cell differentiation. The human lens mainly expresses γC-, γD-, and γS-crystallins.

The mutation patterns in γ-crystallin genes may include missense, insertion, and splice mutations, typically resulting in nuclear and zonular cataracts (Table 4.1) [31–40, 64, 65]. It is thought that γ-crystallin gene mutations contribute to cataract development and progression in a similar way to that of β-crystallin mutations, involving the destruction of protein solubility and stability. For instance, both R36S and R58H mutations in the CRYGD gene have been shown to cause a reduction in protein solubility by changing their surface properties, which may lead to protein deposition and consequently cataracts [36, 37]. Another mutation R14C may increase the sensitivity of CRYGD to sulfhydryl-mediated polymerization, making proteins susceptible to aggregation and thereby resulting in lens opacities [40]. Thus, even in the absence of degeneration or other major structural changes (such as those causing misfolding), a minor change in the lens proteins may also give rise to cataracts.

The membrane protein content is very low in the lens, accounting for less than 1 % of the lens wet weight. But these proteins play an essential role in intercellular signaling and maintenance of lens transparency. In membrane protein genes, cataract-related mutations are commonly seen in gap junction protein (GJP), major intrinsic protein of lens fibers, and lens intrinsic membrane protein-2 (LIM-2).

Cytoskeleton is a network composed of filamentous proteins within a eukaryotic cell, which supports the cell shape and is involved in intracellular transportation, cell division, and motility. In the lens, cytoskeletal proteins include microfilaments, microtubules, and intermediate filaments. Interaction between cytoskeletal proteins and crystallins is important in lens cell differentiation and maintenance of lens transparency.

The development of the lens is under precise spatiotemporal regulation by a series of regulators that mainly include transcription factors and growth factors. In particular, transcription factors regulate the interactions between the ectoderm and the optic vesicles, as well as the induction of lens development, growth, and differentiation, playing crucial roles in the embryonic development of the lens. Genetic mutations in these transcription factors have been linked to both lens opacities and anterior segment developmental anomalies. Mutations in the PITX3, PAX6, FOXE3, EYA1, MAF, and HSF4 genes have been reported to cause hereditary cataracts. Except for HSF4, mutation gives rise to isolated cataracts, while the other mutations often result in cataracts accompanied by other ocular abnormalities that will be discussed in the next section.

The HSF family has six members, i.e., HSF1, HSF2, HSF4, HSF5, HSFY, and HSFX. They are widely expressed in the embryonic and adult lens, reflecting their important roles in the lens development; however, the underlying regulatory mechanism remains unknown [76]. As molecular chaperones, HSFs participate in protein synthesis, assembly, folding, and denaturation. Any abnormality in the structure or expression of HSFs may contribute to the development of cataracts [77].

Mutations in HSF4 are associated with hereditary cataracts with autosomal dominant or recessive inheritance. The former is characterized by childhood onset, typically as lamellar opacity [78], whereas the latter is usually present at birth, manifesting as significant nuclear opacities with partial cortical opacities, or severe total cataract, often complicated with nystagmus [47, 48]. Recently, it has been postulated that HSF4 mutations contribute to cataractogenesis via three pathways: downregulation of γ-crystallins (particularly γS-crystallins) and BFSP expressions, as well as mediation of the loss of posttranscriptional modification of αA-crystallin [79].

This subtype accounts for approximately 30 % of all hereditary cataracts, which can be classified as monogenic or chromosomal disease based on etiology. The monogenic diseases associated with hereditary cataracts may only have ocular conditions, or sometimes be accompanied by systemic abnormalities (Table 4.1 and Table 4.2); while all cases of chromosomal diseases have systemic abnormalities along with cataracts (Table 4.2).