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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Exp Eye Res. 2021 Jun 12;209:108662. doi: 10.1016/j.exer.2021.108662

Inherited Cataracts: Genetic Mechanisms and Pathways New and Old

Alan Shiels *, J Fielding Hejtmancik #
PMCID: PMC8595562  NIHMSID: NIHMS1716186  PMID: 34126080

Abstract

Cataract(s) is the clinical equivalent of lens opacity and is caused by light scattering either by high molecular weight protein aggregates in lens cells or disruption of the lens microarchitecture itself. Genetic mutations underlying inherited cataract can provide insight into the biological processes and pathways critical for lens homeostasis and transparency, classically including the lens crystallins, connexins, membrane proteins or components, and intermediate filament proteins. More recently, cataract genes have been expanded to include newly identified biological processes such as chaperone or protein degradation components, transcription or growth factors, channels active in the lens circulation, and collagen and extracellular matrix components. Cataracts can be classified by age, and in general congenital cataracts are caused by severe mutations resulting in major damage to lens proteins, while age related cataracts are associated with variants that merely destabilize proteins thereby increasing susceptibility to environmental insults over time. Thus there might be separate pathways to opacity for congenital and age-related cataracts whereby congenital cataracts induce the unfolded protein response (UPR) and apoptosis to destroy the lens microarchitecture, while in age related cataract high molecular weight (HMW) aggregates formed by denatured crystallins bound by α-crystallin result in light scattering without severe damage to the lens microarchitecture.

Keywords: Lens, Cataract, Genetics, Crystallin

Introduction

Lens development, structure, and function

The overall function of the eye lens is to transmit and focus images on the retina, which detects the light signals, and carries out some initial processing before transmitting them as nerve impulses to the optic cortex. This function requires that the refractive index within the lens should be relatively constant over distances approximating the wavelength of the transmitted light (Benedek, 1971; Delaye and Tardieu, 1983). This is accomplished by the highly ordered arrangement of lens epithelia and fiber cells lacking organelles and their soluble proteins, especially the crystallins, being highly concentrated and closely packed. Similarly, focusing of light by the lens is dependent on both its overall shape and ability to accommodate and the optical density of its protein constituents throughout the lens.

Surrounded by a basement membrane or capsule, the lens consists of a single layer of anterior epithelial cells that overlie the lens nucleus and cortex. It develops from the lens placode, a thickening of the surface ectoderm overlying the optic vesicle (Fig. 1A). In coordination with optic cup formation, the lens pit invaginates (Fig. 1 B), and eventually closes to form the lens vesicle and separates from the corneal epithelium, which has closed above it (Fig. 1C). During development the epithelial cells divide at the ‘10 and 2 o’clock’ positions of the lens circumference and then migrate or are displaced laterally towards the lens equator where they are they are stimulated by FGF (Dawes et al., 2018) and possibly hypoxia (Brennan et al., 2020; Brennan et al., 2018) to invert and elongate within the bow-region to form differentiated fiber cells (Fig. 1D). These secondary fiber cells layer around the primary fiber cells in the central lens nucleus with their footplates meeting on the lens sutures. This developmental process is controlled by a complex set of physical and inductive factors (Bassnett and Sikic, 2017; Chauhan et al., 2015).

Figure 1.

Figure 1.

Simplified diagram of lens development and structure. A. lens placode formation over the optic vesicle B. invagination of the optic cup and formation of the lens pit C. pinching off of the lens vesicle from the overlying cornea D. structure of the adult lens including the primary and secondary fiber cells, sutures, overlying anterior epithelia and surrounding lens capsule.

Early in this process fiber cells begin to synthesize large amounts of lens crystallins and other specialized proteins before degrading their organelles, including nuclei and mitochondria, to minimize light scattering. Organelle removal appears to involve the ubiquitin-proteasome pathway (Wride, 2011) as well as autophagy (Costello et al., 2013), perhaps mediated through p27 for denucleation (Rowan et al., 2017). This process begins in embryogenesis and continues at a decreasing rate through development and the rest of the individual’s life, with succeeding lens fiber cells overlying their predecessors, eventually forming the onion-like structure of the lens nucleus and cortex. Both the organelle loss and precise layering of fiber cells are structural requirements for lens transparency that is further sustained by metabolic activity of the anterior epithelium.

Because fiber cells lack the ability to repair or replace damaged or modified proteins, the lens crystallins and other protein constituents must be extremely stable since they must survive for the entire lifespan of the organism. A correlative requirement is that the lens must possess robust metabolic pathways to maintain homeostasis, in particular to combat oxidative damage by maintaining a strong reducing environment (Ganea and Harding, 2006) (Kantorow et al., 2004), and to inhibit glycation products and resist osmotic insults (Linetsky et al., 2008). Lacking mitochondria, the central nuclear fiber cells rely primarily on glycolysis for energy to maintain homeostasis. In addition, they are metabolically supported by the anterior epithelium via a gap-junction mediated microcirculation of ions, fluids, and small molecules throughout the avascular (Gao et al., 2018). Disruption of any part of the lens’s precisely configured anatomy and integrated physiology will degrade lens clarity and optical quality resulting in cataracts.

Lens opacities and cataracts

Disruption of the lens structure and organization such as vacuole formation and fiber cell degeneration cause light-scattering, as do HMW protein aggregates larger than 1000 Å in size. (Shiels and Hejtmancik, 2017). The crystallins comprise over 90% of soluble lens proteins and their short-range ordered packing in a homogeneous phase supports lens transparency.

Cataracts can be categorized by the age they are diagnosed, although diagnosis almost always lags behind the occurrence of lens opacity, sometimes significantly. Congenital and infantile cataracts present between birth and two years of age followed by juvenile cataracts being diagnosed between years two and ten and then presenile cataracts and finally age-related cataracts after 45–55 years of age. Cataracts with a similar age of onset might have different causes. For example, congenital cataracts might be inherited or caused by an intrauterine insult such as viral or parasitic infections, whereas age-related cataracts are associated with environmental insults accumulated over decades with susceptibility to these insults strongly influenced by genetic risk factors.

Since opacity resulting from a mutant crystallin would be expected to occur in lens cells containing high concentrations of the affected crystallin, mutations in various genes show distinct but overlapping patterns of cataract roughly following their expression (Shoshany et al., 2020). Thus, mutations in the γ-crystallins, which are synthesized at high levels early in lens development in fiber cells that will form the central nucleus, are frequently associated with some form of nuclear cataracts. This doesn’t hold in all cases as mutations in different genes can cause similar cataracts and even the same mutation in one gene can cause a variety of cataract presentations (Scott et al., 1994). However overall, severe mutations in crystallins or other lens proteins that directly cause protein aggregation or damage lens cells tend to result in congenital cataracts, while less severe variants that merely increase susceptibility to damage from environmental stresses such as hyperglycemia, ultraviolet light, or oxidative stress tend to contribute to age related cataract.(Hejtmancik and Smaoui, 2003). A correlate of this is that congenital cataracts tend to be inherited in a Mendelian fashion with high penetrance, while age-related cataracts tend to be complex and varied, with contributions both from both multiple genes and environmental factors.

Congenital cataracts

Estimates of the incidence of congenital cataracts vary from 12 to 136 per 100,000 births, with between 8.3 and 25 percent of congenital or infantile cataracts being hereditary (Francois, 1982; Gilbert and Foster, 2001; Haargaard et al., 2004; Haargaard et al., 2005; Merin, 1991; Stoll et al., 1992). The fraction of inherited cataract is lower in less developed countries, probably because of a higher risk of infectious disease and other environmental causes. Hereditary Mendelian cataracts are most frequently inherited as an autosomal dominant trait, but can also show autosomal recessive, or X-linked inheritance.

In addition to age of onset, cataracts can also be classified by their clinical appearance and location within the lens. The Merin classification is the most common, with cataracts divided into polar (anterior or posterior), zonular (nuclear, lamellar, sutural, etc.), total (mature or complete), and capsular or membranous (Merin and Crawford, 1971). Congenital cataracts may be isolated or associated with additional anterior chamber anomalies such as microcornea, microphthalmia, or even aniridia, and may even occur as part of multisystem genetic syndromes including chromosome abnormalities, developmental defects, or metabolic disorders, and this can also be used in their classification (Lin et al., 2016). Many mutations show isolated cataracts in some patients while in others, even in the same family, they may be associated with defects in the anterior segment or entire eye.

Age related cataract

Age related cataracts are multifactorial, with the accumulated damage induced by various environmental effects acting over time on the underlying genetic predisposition. They are extremely common and usually progressive. Crystallins acquire numerous modifications with aging of the lens, including proteolysis, deamidation, disulfide bridges, phosphorylation, nonenzymatic glycosylation, carbamylation, and racemization of aspartic acid (Sharma and Santhoshkumar, 2009) (Lampi et al., 2014; Ma et al., 1998). Most of the changes are caused or accelerated by ultraviolet light exposure, oxidation, or osmotic stress, the same risk factors that have been identified in epidemiological studies of cataractogenesis. In addition, the chemical modifications identified in lenses with cataracts are also seen in in vitro or in vivo model systems subjected to similar stress factors (Ottonello et al., 2000).

As crystallins comprise over 90% of the soluble proteins, they have been the most highly studied proteins in the aging lens. Humans have three major classes of crystallins, α-, β- and γ-, each of which comprise a gene family. The β- and γ-crystallins share a very stable two domain structure containing four Greek key motifs (Jaenicke and Slingsby, 2001) and together form a conserved protein family, the βγ-crystallins. As the lens ages, the βγ-crystallins are modified, especially under the influence of environmental stress, and start to open up their stable Greek key structures, eventually forming high molecular aggregates. Intermediate stages of in this process are bound by α-crystallins, which possess a chaperone-like activity (Lampi et al., 2014) (Rao et al., 1995). Although some modifications decrease the efficiency of binding by α-crystallin, such complexes maintain the solubility of the denatured βγ-crystallins, reducing light scattering. They are not recycled but rather are held in the α-crystallin complexes that then increase in size over time as more damaged βγ-crystallins are bound, eventually forming high molecular weight aggregates (HMW) that are large enough to scatter light (Datiles et al., 2008; Rao et al., 1995). Although α-crystallins are highly expressed in the lens, over time free α-crystallin is exhausted in the anucleate lens fiber cells and the high molecular weight aggregates become large enough to precipitate, joining the insoluble protein that increases with age and in cataractous lenses (Datiles et al., 2008; Datiles et al., 2016; Minaeva et al., 2020). The increasing denatured protein damages the lens cells and contributes to cataracts not only by the protein aggregates scattering light, but eventually also by the toxic effect of the denatured protein aggregates on lens fiber cells causing cell death and disrupting cellular architecture (Ma et al., 2011; Wang et al., 2007a). In a similar fashion, mutations in channel proteins and others that maintain lens homeostasis can damage the intracellular environment and protein constituents of lens cells, contributing to age related cataract.

While age related cataracts do not have as severe an impact on affected individuals as congenital cataracts, they have a much greater overall population burden because of their high frequency. They are the leading cause of blindness worldwide, afflicting 15.2 million persons Lancet (GBD 2019 Blindness and Vision Impairment Collaborators; Vision Loss Expert Group of the Global Burden f Disease Study, 2021), and the leading cause of low vision in the United States (Congdon et al., 2003). Cataract surgery is the most frequently performed outpatient surgery, with roughly 5% of the US population over 40 undergoing cataract extraction. Because patients with age related cataracts are elderly, it has been proposed that the demand for cataract surgery could be decreased by about 45% if the age-at-onset could be delayed by ~10 years through the discovery of medical treatments (Kupfer, 1984).

Environmental effects on the risk of age cataracts varies with the sub-type of lens opacity. The risk of nuclear cataracts is increased by elevated blood glucose levels, cigarette smoking or chronic exposure to wood smoke, or obesity (Chang et al., 2011; Foster et al., 2003; Leske et al., 1991; Lu et al., 2012; Ye et al., 2012), whereas cortical cataracts are associated with ultraviolet light and hyperglycemia (Brown and Hill, 1987; Foster et al., 2003; Hennis et al., 2004; Italian-American_Cataracy_Study_Group, 1991; Machan et al., 2012) and posterior sub-capsular cataracts (PSC) are increased with smoking, diabetes, radiation, and certain drugs including corticosteroids (Abe et al., 2012). That nuclear, cortical and posterior subcapsular cataracts have differing environmental causes is consistent with their having different pathogenic pathways to opacification that all end with cataracts and suggests that the genetic causes of these types of age-related cataract might also vary.

There is also epidemiological support for a genetic contribution to age-related cataracts, including (McCarty and Taylor, 2001) (Italian-American_Cataracy_Study_Group, 1991) (Leske et al., 1991). Having a sibling with cataracts increases an individual’s risk for age-related cataract threefold (Leibowitz et al., 1980) with the genetic contribution accounting for 35–48% of nuclear cataract, 53–75% of nuclear and cortical cataract combined (Hammond et al., 2001; Klein et al., 2001), and 20–39% of cataract overall (Benito et al., 2016).

Genetics of Mendelian Cataracts

Although most Mendelian isolated cataracts are diagnosed in the first year of life, some present as late as early adulthood. Currently, there are about 71 mapped loci for cataract with 56 causative genes identified so far (Table 1). As well as isolated cataracts, inherited cataracts can be part of multisystemic diseases (Hejtmancik et al., 2001). In addition, some cataract mutations can cause extralenticular effects as part of a developmental sequence. An example of this is crystallin mutations causing severe early disruption of lens development, which then impacts development of the anterior chamber and secondarily causes microcornea or in extreme cases microphthalmia. Finally, early onset severe cataracts can cause visual deprivation during the early critical period of development, thus blocking development of the nerve pathways linking the retina to the optic cortex, resulting in nystagmus or even blindness.

Table 1. Genes and Loci Implicated in Mendelian Cataracts.

1: Lens Crystallins, 2: Transcription and Developmental Factors, 3: Gap Junction Proteins (Connexins), 4: Membranes, Channels and Transporters, 5: Beaded Filament, Intermediate Filaments and Cytoskeleton, 6: Chaperones and Protein Degradation, 7: Mitochondria and Metabolic 8: Other, 9: Unknown locus. Only genes implicated in isolated cataracts are listed. A more complete compilation including individual mutations can be found in Cat-Map: https://cat-map.wustl.edu/.

Locus Gene INH MIM no. Gene/Locus MIM no. Associated extralenticular phenotypes Class Reference
1 1pter-p36.13 RP1–140A9.1 AD 115665 NA Volkman 8 (Eiberg et al., 1995)
2 1p36.32 PANK4 AD NA 606162 7 (Sun et al., 2019)
3 1p36.13 EPHA2 AD/AR 116600 176946 Susceptibility to age-related cortical cataract, 2 (Shiels et al., 2008)
4 1p32 FOXE3 AR 612968 601094 With or without microcornea, microphthalmia, aphakia, coloboma 2 (Semina et al., 2001)
5 1q21.1 GJA8 AD/AR 116200 600897 With or without microcornea 3 (Shiels et al., 1998)
6 1q12–24 MYOC Sporadic 601652 5 (Li et al., 2016)
7 1q25–31 ? AD 9 (Wang et al., 2007b)
8 1q41 IARS2 AR 616007 612801 skeletal dysplasia, GH deficiency, sensory neuropathy in some 7 (Li et al., 2018)
9 2pter-p24 CTRCT29 AD 115800 NA 9 (Gao et al., 2005)
10 2p12 CTRCT27 AD 607304 NA 9 (Khaliq et al., 2002)
11 2q33.3 CRYGD AD 115700 123690 With or without microcornea 1 (Heon et al., 1999)
12 2q33.3 CRYGC AD 604307 123680 With or without microcornea 1 (Heon et al., 1999)
13 2q33.3 CRYGB AD 615188 123670 1 (AlFadhli et al., 2012)
14 2q33.3 CRYGA AD 123660 1 (Li et al., 2016)
15 2q34 CRYBA2 AD 115900 600836 1 (Reis et al., 2013)
16 3p21.31 FYCO1 AR 610019 607182 6 (Chen et al., 2011)
17 3q22.1 BFSP2 AD 611597 603212 Myopia 5 (Jakobs et al., 2000)
18 3q27.3 CRYGS AD 116100 123730 1 (Zhai et al., 2017)
19 3q28 P3H2 AR 614292 610341 Myopia, ectopis lentis, vitreoretinal degeneration 5 V7(Khan et al., 2015b)
20 4p16.1 WFS1 AD 116400 606201 Wolfram syndrome (DIDMOAD) 4 (Berry et al., 2013)
21 5q22 WDR36 Sporadic 609887 609669 POAG 2 (Li et al., 2016)
22 6p24 GCNT2 AR 110800 600429 Adult i blood group phenotype 4 (Yu et al., 2001)
23 6p12-q12 CTRCT28 ? 609026 NA Age-related cortical cataract, susceptibility to 9 (Iyengar et al., 2004)
24 6p21.31 LEMD2 AR 212500 616312 4 (Boone et al., 2016)
25 7q21-q31 ? AR 9 (Kaul et al., 2010b)
26 7q21/2 CYP51A1 AR 601637 hepatic failure, developmental delay 4 (Aldahmesh et al., 2012)
27 7q34 AGK AR 614691 610345 Senger’s syndrome 4 (Aldahmesh et al., 2012)
28 8q13.3 EYA1 AD 602588 601653 Branchio-oto-renal syndrome, ASD 2 (Azuma et al., 2000)
29 9p22.1 RRAGA AD 612194 6 (Chen et al., 2016)
30 9q13-q22 CTPL1 AR 605749 NA 9 (Heon et al., 2001)
31 9q21.12-q21.13 TRPM3 608961 POAG 4 (Bennett et al., 2014)
32 9q22.33 TDRD7 AR 613887 611258 2 (Lachke et al., 2011)
33 10p15.1 AKR1E2 AR 617451 7 (Aldahmesh et al., 2012)
34 10p13 VIM AD 116300 193060 5 (Muller et al., 2009)
35 10p23.31 RNLS AR 609360 7 (Aldahmesh et al., 2012)
36 10q23.13 SLC16A12 AD 612018 611910 4 (Kloeckener-Gruissem et al., 2008)
37 10q24.2 DNMBP AR 618415 611282 5 (Ansar et al., 2018)
38 10q24.32 PITX3 AD 610623 602669 Anterior segment mesenchymal dysgenesis, microphthalmia, neurodevelopmental abnormalities 2 (Semina et al., 1998)
39 11q22.3 CRYAB AD/AR 613763 123590 Myopathy, multiple types 1 (Vicart et al., 1998)
40 12q13.3 MIP AD 615274 154050 4 (Berry et al., 2000)
41 12q24.2-q24.3 CTRCT37 AD 614422 NA 9 (Berry et al., 2011)
42 13q12.1 GJA3 AD 601885 121015 3 (Mackay et al., 1999)
43 13q34 COL4A1 AD 120130 5 (Xia et al., 2014)
44 14q11.2 SLC7A8 AR 604235 4 (Knopfel et al., 2019)
45 14q22-q23 CTRCT32 AD 11565000 NA 9 (Pras et al., 2006)
46 15q21-q22 CTRCT25 AD 605728 NA 9 (Vanita et al., 2000)
47 16q21 HSF4 AD/AR 116800 602438 2 (Bu et al., 2002)
48 16q22-q23 MAF AD 610202 177075 With or without microcornea 2 (Jamieson et al., 2002)
49 17p13.3 TSR1 611214 8 (Yu et al., 2020)
50 17p13 CTAA2 AD 601202 NA 9 (Berry et al., 1996)
51 17q11.2 CRYBA1 AD 600881 123610 1 (Kannabiran et al., 1998)
52 17q12 UNC45B AD 616279 611220 6 (Hansen et al., 2014)
53 17q24 CCA1 AD 115660 NA 9 (Armitage et al., 1995)
54 19p13.2 LONP1 AR 605490 Also CODAS syndrome 7 (Khan et al., 2015a)
55 19q13 CTRCT35 AR 609376 NA 9 (Riazuddin et al., 2005b)
56 19q13 ADPCZNC AD 9 (Li et al., 2006b)
57 19q13.13 WDR87 AR ? (Khan et al., 2015a)
58 19q13.1–13.2 SIPA1L3 AR 616851 616655 2 (Greenlees et al., 2015)
59 19q13.41 LIM2 AR 615277 154045 4 (Pras et al., 2002)
60 19q13-qter ? AD 9 (Zhao et al., 2011)
61 20p13 ADPCZNC AD 9 (Li et al., 2006a)
62 20p12.1 BFSP1 AR 611391 603307 5 (Ramachandran et al., 2007)
63 20q11.21 CHMP4B AD 605387 610897 6 (Shiels et al., 2007)
64 20q11 NCOA6 AD 605299 2 (Kandaswamy et al., 2020)
65 21q22.3 CRYAA AD/AR 604219 123580 With or without microcornea, susceptibility to age-related nuclear cataract 1 (Litt et al., 1998)
66 21q22.3 LSS AR 616509 600909 4 (Zhao et al., 2015)
67 22q11.23 CRYBB3 AD/AR 609741 123630 1 (Riazuddin et al., 2005a)
68 22q11.23 CRYBB2 AD 601547 123620 With or without microcornea 1 (Litt et al., 1997)
69 22q12.1 CRYBB1 AD/AR 611544 6009291 1 (Mackay et al., 2002)
70 22q12.1 CRYBA4 AD 610425 123631 1 (Billingsley et al., 2006)
71 Xp22.13 NHS X-linked 302200 300457 Nance-Horan (cataract dental) syndrome 2 (Burdon et al., 2003)

Genetic causes of Mendelian cataracts can be grouped by the cellular processes of which they are a part, suggesting that these pathways are critical for lens development or homeostasis. Currently, of unrelated families with inherited cataracts the genes and functional groups most frequently implicated are crystallins (33%), developmental or transcription factors (26%), connexins (18%), membrane proteins and transporters (11%), and intermediate filament proteins and chaperones with 4% each (Shoshany et al., 2020), (Fig. 2).

Figure 2.

Figure 2.

Fraction of cataract families with mutations in genes belonging to specific pathways, processes, or protein families. Crystallins are the most commonly mutated genes in congenital cataract, followed closely by developmental factors, then connexins, and membrane proteins/channels. The remaining known groups and pathways contribute less than 10%. Cataract frequencies are compiled from CAT-MAP: https://cat-map.wustl.edu/.

Crystallin Mutations

The key role of the crystallins in maintaining lens transparency and ability to focus has long been appreciated (Mörner, 1894). Their importance in lens biology is emphasized by mutations in crystallins being the most commonly identified cataract mutations, although this might also reflect their being preferentially screened by investigators searching for the cause of inherited cataracts.

α-Crystallins

α-Crystallins function in the lens not only in the traditionally recognized role for crystallins, as highly expressed structural proteins needed for transparency and refraction, but also as chaperones that help to shield the lens from light scattering and damage by denatured βγ-crystallins (Horwitz, 2003). In addition to their chaperone activity, α-crystallins mediate formation of the lens specific beaded filaments (Prescott et al., 1996), decrease PI3K, AKT, and ERK activation (Ruan et al., 2020), protect mitochondria from oxidative stress (McGreal et al., 2013), and regulate lysosomal activity by interacting with ATP6V1A and mTOR (Cui et al., 2020), although how mutations in CRYAA affect these activities has not been studied in detail. Mutations resulting in a lack of expression of functional αA- and αB-crystallins can produce autosomal recessive cataracts, suggesting that decreased levels of functional α-crystallin are sufficient to maintain lens transparency. Examples include a p.W9X mutation that is predicted to cause nonsense mediated decay and thus functional absence of the mutant allele without changing CRYAA expression from the normal gene (Pras et al., 2000).Similarly, p.R54C mutation in CRYAA causes total congenital cataracts in homozygotes, but heterozygote carriers only show mild punctate opacities (Khan et al., 2007). Additionally, three families segregating CRYAB mutations causing autosomal recessive cataracts have been reported (Jiao et al., 2015; Safieh et al., 2009).These observations suggest that even decreased levels of α-crystallin can provide sufficient chaperone-like activity and structural crystallin packing to establish and maintain lens transparency during childhood, although they might increase susceptibility to environmental damage and age related cataract (Ma et al., 2016a), consistent with results in αA-crystallin knock-out mice (Brady et al., 1997). Conversely, autosomal dominant cataracts, which are often caused by nonconservative missense mutations, probably produce a deleterious mutant α-crystallin protein that damages the lens homeostasis or blocks activity of normal α-crystallin in a dominant negative mechanism. Because CRYAA is expressed early in lens development, CRYAA related cataracts are often associated with microcornea, probably related to early interactions between the lens and the developing anterior chamber.

Because αA- and αB-crystallin function almost identically in vitro and both associate together to form large multimeric complexes one might anticipate that mutations in CRYAB would present like CRYAA mutations, at least in the lens. However, CRYAB mutations causing decreased chaperone ability and stability with aggregation and precipitation when stressed caused a myofibrillar myopathy with only “discrete” cataracts (Vicart et al., 1998), similar to the phenotype of the αB-crystallin knockout mouse, which has a myopathy but no cataracts (Brady et al., 2001). Since CRYAA is highly lens specific but CRYAB is highly expressed in myocytes, in which it stabilizes desmin, the occurrence of myopathy with CRYAB but not CRYAA mutations is not unexpected (Brady et al., 2001). However, mutations in CRYAB can also cause autosomal dominant and recessive cataracts without myopathy (Jiao et al., 2015; Liu et al., 2006).

βγ-Crystallins

In contrast to the α-crystallins, most mutations in the βγ-crystallins act by encoding an unstable crystallin that denatures, either immediately or when acted on by an environmental stress, and is then bound by α-crystallin to form high molecular weight aggregates that scatter light and eventually precipitate when the α-crystallin is exhausted, causing lens cell damage and cataract. Exceptions to this pathogenesis are autosomal recessive cataracts including a p.C185EfsX33 mutation in CRYBA1 (Khan et al., 2015a), a p.M1K mutation in CRYBB1 in one family (Meyer et al., 2009), a p.N58TfsX106 CRYBB1 mutation in 3 families (Aldahmesh et al., 2012; Cohen et al., 2007; Khan et al., 2012), a p.71S CRYBB1 mutation in one family (Lenfant et al., 2017), a p.K252R CRYBB1 mutation in one family (Aksay et al., 2020), a p.G147V mutation in CRYBA4 in one family (Chen et al., 2017), and a p.(G65R) CRYBB3 mutation in two families (Riazuddin et al., 2005a). The reason for the relative scarcity of autosomal recessive mutations in the β-crystallins and their absence in γ-crystallins is unclear. However, the presence of recessive mutations that would be expected to result in the absence of a protein product in some β-crystallins suggests that these β-crystallins, if not γ-crystallins, might also have a molecular functions beyond that of structural proteins.

The γ-crystallins are highly fiber cell specific and expressed in large quantities in the primary fibers and correspondingly, γ-crystallin mutations tend to result in nuclear or nuclear zonular cataracts, although their specific phenotypes may vary. Similarly, β-crystallin mutations can cause a wide variety of cataract phenotypes including nuclear and zonular, dense to pulverulent opacities sometimes involving the lens sutures, or cerulean cataracts. A wide variety of cataract phenotypes can result from the same mutation, as exemplified by a c.119_123dup mutation in CRYGC, with cataracts of similarly variable severity in humans (Scott et al., 1994) and in mice transgenic for this mutation (Ma et al., 2011).

In addition to mutations that destabilize the protein fold of the βγ-crystallins, three mutations in γD-crystallin result in normal structure and stability, but alter the hydrophobicity of the molecule’s surface, decreasing its solubility or enhancing the protein-to-protein attraction of monomers so that they separate from the aqueous solution (Pande et al., 2001). These include a p.(P23T) mutation that increases inter-protein hydrophobic interactions, a p.R36S mutation that actually causes crystallization of the protein in lens cells (Kmoch et al., 2000), and a p.(R14C) mutation in which the mutant cysteine-14 participates in thiol-thiol bonds leading to precipitation (Pande et al., 2000). Thus, βγ-crystallin mutations can cause aggregation and cataract without major changes in protein conformation or stability.

Membrane Proteins and Constituents

Enzymes synthesizing membrane constituents

The tremendous elongation of lens epithelial cells as they differentiate into fiber cells requires a great burst of synthesis of membrane lipids and proteins. Thus, mutations in genes encoding protein constituents of membranes or membrane-related proteins are responsible for a large fraction of inherited cataracts. Disruptions in genes that encode enzymes involved in the biosynthesis of membrane lipids have been shown to cause inherited cataracts. These include lanosterol synthase (Zhao et al., 2015) and CYP51A1, which are needed for synthesis of cholesterol, a component of fiber cell membranes, and acylglycerol kinase, which is needed to synthesize lysophosphatidic and phosphatidic acid (Aldhamesh et al., 2012). GCNT2, which catalyzes I-branches of poly-N-acetyllactosaminoglycans on cell membranes and determines the adult I blood type, is also implicated in recessive cataracts (Yu et al., 2003)

Membrane channel, transporter, and junction proteins

Some membrane proteins also function in ion or solute transport and are responsible for the lens circulation that is critical for nutrition and maintenance of the lens fiber cells (Gao et al., 2018). Among these are gap junctions, which function in nutrition and intercellular communication of lens cells. The two predominant gap junction proteins in the lens are GJA3 and GJA8 (connexins 46 and 50). One mutation, p.(P88S) in GJA8 cannot form functional gap junction channels (Berthoud et al., 2003), and when incorporated into gap junctions with wild type monomers they inhibit channel function in an apparent dominant negative mechanism (Minogue et al., 2005). Other mutants are completely unable to form gap junction channels (Pal et al., 2000). GJA3 and GJA8 mutations both cause mostly nuclear or nuclear lamellar cataracts.

SLC16A12, important for monocarboxylic acid transport, when mutated can cause autosomal dominant cataracts associated with microcornea and renal glycosuria in some cases (Kloeckener-Gruissem et al., 2008), as can mutations in SLC7A8, an amino acid transporter (Knopfel et al., 2019). Aquaporin 0 (AQP0 or MIP), in the aquaporin water transporter family, is the predominant protein in lens membranes, and mutations in it have been implicated in about 5% of inherited cataracts. The p.(E134G) and p.(T138R) mutations in AQP0 interfere both with movement of AQP0 to the plasma membrane as well as water channel activity by normal AQP0, thus acting in a dominant negative fashion, consistent with their autosomal dominant inheritance pattern (Francis et al., 2000). In addition, mutations in ABCA3, an ATP-binding cassette lipid transporter also implicated in respiratory disease, TMEM114, a transmembrane protein, LIM2, a lens-specific intrinsic membrane protein, similar to TMEM114 that is implicated in cell junctions and/or fusions (Pras et al., 2002), and DNMBP, a guanine nucleotide exchange factor that regulates the configurations of cell junctions (Ansar et al., 2018) can also cause congenital cataracts. Mutations in TRPM3, a calcium channel, cause punctate cortical or posterior sub-capsular cataracts sometimes associated with POAG, probably through increased calcium entry leading to degeneration of lens cells (Bennett et al., 2014; Zhou et al., 2021). Also, fitting loosely into this group is WFS1, a transmembrane protein localized to the endoplasmic reticulum and better known for causing Wolfram syndrome or Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness (DIDMOAD) (Berry et al., 2013).

Cytoskeletal proteins

BFSP1 (filensin, CP115) and BFSP2 (phakinin, CP49), distant members of the intermediate filament protein family, are uniquely expressed in lens fiber cells. With the chaperone activity of α-crystallins they combine to make beaded filaments, which are also only found in lens fiber cells. Missense mutations in BFSP1 and BFSP2 are associated with nuclear, lamellar, and sutural autosomal dominant cataracts. However, frameshift and nonsense mutations that would result in the absence of the gene product cause recessive cortical cataracts.

Mutations in NHS, an actin remodeling regulator, usually cause the X-linked Nance Horan syndrome, comprising dental abnormalities, cataracts, dysmorphic facies and occasionally mental retardation but can also cause isolated cataracts.

Transcription and developmental factors

PAX6, a paired box and homeobox domain protein, is one of the earliest acting transcription factors in eye development. Although most mutations in PAX6 result in developmental defects of the entire eye field, including anophthalmia, aniridia and Peter’s anomaly, one mutation affecting only the C-terminal PST domain causes lamellar cataract with corneal dystrophy occurring later in life (Glaser et al., 1994). Some transcription factors such as VSX2, MAF, FOXE3, EYA1, and PITX3 acting later in lens development tend to cause isolated cataracts, although they can also contribute to variable malformations of the anterior segment that range from mild microcornea to severe anterior segment mesenchymal dystrophy (ASMD). As opposed to the growth factors described above, mutations in the heat-shock transcription factor HSF4 that controls expression of lens αB-crystallin and other heat shock proteins in the lens (Somasundaram and Bhat, 2004), cause isolated cataracts. The autosomal dominant cataracts are lamellar or zonular and usually result from missense mutations in the α-helical DNA-binding domain (Bu et al., 2002), while the recessive cataracts are usually caused by null mutations outside the highly conserved DNA-binding domain. They range from nuclear with some cortical involvement (Forshew et al., 2005) to total lens opacities with secondary nystagmus indicating a prenatal or early postnatal onset (Smaoui et al., 2004). NCOA6 is a transcriptional activator that has been associated with hormone-dependent coactivation of retinoid among other receptors, and heterozygous mutations have been described in three siblings with cataracts.

While not a transcription factor, the ephrin receptor tyrosine kinase EPHA2 is involved in developmental processes in both the eye and the nervous system. EPHA2 mutations can result in both dominant and recessive congenital cataracts and have also been implicated in age related cataracts.(Jun et al., 2009; Kaul et al., 2010a; Shiels et al., 2008; Sundaresan et al., 2012; Tan et al., 2011; Zhang et al., 2009).

RNA stability and other biological processes highly active in the lens

As lens epithelia differentiate into fiber cells, they must synthesize not only large amounts of lipids for membranes, but also massive amounts of lens crystallins and other proteins, putting significant stress on the protein synthetic apparatus. This includes TDRD7, a component of RNA granules active in RNA processing expressed in many tissues but shown to cause isolated hereditary cataracts. Similarly, mutations in the ribosomal maturation factor TSR1 have been implicated in congenital cataracts. While not strictly an isolated cataract, the hyperferritinemia-cataract syndrome includes asymptomatic hyperferritinemia in the absence of iron overload and cataracts. Mutations in the iron responsive element of FTL, a stem loop structure in the 5’ untranslated region of the mRNA that in the absence of iron binds the cytoplasmic iron regulatory protein to inhibit FTL translation. Loss of this translational control increases expression of FTL to levels approaching that of a crystallin and subsequent crystallization ferritin in the lens resulting in cortical and nuclear cataract. This emphasizes that lens crystallins must be exceptionally soluble to remain in solution in the fiber cell cytoplasm without precipitation or dysfunction.

Chaperones, autophagy and protein degradation

During lens development there is revision of the lens structure itself. Part of this occurs when lens epithelia transition into cortical fibers, during which not only is there massive synthesis of membrane lipids and proteins, but also loss of organelles such as the mitochondria and nuclei, which requires massive protein and organelle degradation. Early speculation that autophagy was important in this process arose when progressive posterior polar/subcapsular cataracts were associated with mutations in CHMP4B, a subunit of the endosomal sorting complex required for transport-III machinery, important for membrane remodeling and scission (Shiels et al., 2007), and autosomal recessive congenital cataracts were linked with mutations in the scaffolding protein FYCO1, important in transport of autophagic vesicles by microtubules (Chen et al., 2011). The importance of autophagy in lens development was supported morphologically by identification of autophagic vesicles containing organelles being degraded in developing lens fiber cells (Brennan et al., 2012), and genetically by the association of mutations in RRAGA, a GTPase active in the TORC1 pathway with congenital nuclear cataracts (Chen et al., 2016). Unexpectedly, ablation of Gja8b in zebrafish was found to decrease macroautophagy causing cataracts, which could be relieved by the autophagy stimulator rapamycin (Ping et al., 2021). In addition, autophagy-independent mechanisms for lens organelle degradation involving DNASE2B and phospholipases in the phospholipaseA/acyltransferase (PLAAT) family have been discovered (Morishita et al., 2021). However, it remains to be determined if DNASE2B and/or PLAAT gene variants are associated with cataracts. Finally, beyond the chaperone action of α-crystallin, mutations in UNC45B, a co-chaperone with HSP90, have been associated with juvenile subcapsular and central cataracts emphasizing the importance of chaperones in the lens fibers, which lack the capability to turn over proteins.

Collagens and Extracellular Matrix

Mutations in collagens are known to cause Stickler syndrome, Alport syndrome, Knobloch syndrome, and epidermolysis bullosa, all of which can include cataracts. However, a novel mutation in COL4A1, a prominent component of the lens capsule, has been reported to cause autosomal dominant congenital nuclear cataracts (Xia et al., 2014). In addition, a c.297delC (p.G100AfsX104) mutation in P3H2, a prolyl 3-hydroxylase active in collagen crosslinking has also been implicated in autosomal recessive cataracts (Kandaswamy et al., 2020). Mutations in MYOC, which might also fit into this group, have been described in sporadic nuclear congenital cataracts (Li et al., 2016).

In addition, potential novel cataract pathways include Mitochondria and/or intermediary metabolism such as PANK4, AKR1E2, IARS2, RNLS, along with miRNAs and lncRNAs such as implicated for the Volkmann cataract.

Genes Associated with Age Related Cataract

Mendelian childhood and presenile cataracts

While, as stated above, most congenital cataracts are inherited in a highly penetrant Mendelian fashion, some childhood and presenile cataracts also show Mendelian inheritance, a subset of which are progressive. These are often caused by mutations in the same set of genes that cause congenital cataract. Among these are mutations in BFSP2, HSF4 (including the classic progressive childhood Marner cataract), EPHA2, CRYAA, CHMP4B, GJA8, SLC16A12, CRYGD, CRYBA2, CRYBA3, LIM2, and PITX3. In addition, the progressive Volkmann cataract, and the CAAR locus are linked to familial adult onset pulverulent cataracts. As mentioned, different mutations in the same gene can cause either progressive or congenital cataracts, but identical mutations in the same gene can also cause both types of cataract. For example, two of the 15 families described with a p.(Q155X) mutation in CRYBB2 show progressive cataracts, with the rest having congenital cataracts. This suggests that modifying genes or perhaps a stochastic process might play a role in cataractogenesis. Other than the nonsense mutations in CRYBB2 and SLC16A12 and the frameshift mutations in PITX3, most mutations associated with late onset or progressive cataracts are missense mutations that might retain some level of function or stability of the original protein, suggesting a correlation between the severity of a mutation with the timing and phenotype of the cataract it causes.

Examples of this include the p.(G18V) and p.(G18D) CRYGS mutations, both of which are associated with progressive childhood cataracts (Sun et al., 2005; Zhai et al., 2017). While the G18V and D18G CRYGS protein folds are similar or identical to that of native CRYGS protein, both mutants are destabilized at even low levels of chemical or thermal stress (Ma et al., 2009), which is accompanied by increased binding of the p.G18V protein by CRYAB under even relatively benign conditions (Kingsley et al., 2013). This is in contrast to mutations that completely destabilize the protein (Talla et al., 2008) or that do not result in the protein being bound by α-crystallin (Moreau and King, 2012; Rajaraman et al., 1998). This suggests that a mutation that disrupts a protein’s structure or function completely might cause Mendelian congenital cataracts with high or complete penetrance, whereas, in contrast, a variation causing mild protein damage might, especially when coupled with environmental insults, contribute to Mendelian progressive or even complex age-related cataracts.

Because most mutations contributing to age related cataracts have relatively low penetrance and late onset, and often work in concert with other genetic factors and environmental stress, linkage analysis is not feasible for their identification. For this reason, genetic association approaches are most often used to identify these genes and loci, either genome wide or using loci suggested by animal and/or epidemiological studies.

Association studies

There are a number of examples of genes in which specific variations can cause either in Mendelian congenital or age-related cataracts depending on the severity of the mutations involved. One of these is the galactokinase gene (GALK1), deficiency of which results in accumulation of galactitol leading to osmotic swelling and death of lens cells causing autosomal recessive cataracts. Parents of patients with GALK1 deficiency, who are heterozygous carriers, have an increased risk for age related cataracts (Skalka and Prchal, 1980) (Stambolian et al., 1986; Stevens et al., 1989). Similarly the “Osaka” variant, a p.A198V mutation in GALK1 encodes an unstable GALK1 protein with low levels of functional galactokinase that results in an increased incidence of cataracts in Japanese adults (Okano et al., 2001). In a similar fashion, hyperglycemia and diabetes are known to increase the risk of age-related cataract, and susceptibility to diabetic cataracts is associated with a Z allele of the polymorphic microsatellite in the 5’-flanking sequence of the aldose reductase gene (Lee et al., 1995; Lee et al., 2001).

A similar example of mutations resulting in cataracts of varying onset and severity is the creatine transporter SLC16A12, mutations in which can also cause renal glycosuria. A p.(Q215X) nonsense mutation that impairs transport of the protein product to the plasma membrane is associated with juvenile cataracts, microcornea, and glycosuria (Castorino et al., 2011; Kloeckener-Gruissem et al., 2008), while four missense mutations in SLC16A12 are increased in individuals with age related cataract (Staubli et al., 2017). The EPHA2 gene maps to the linkage region on chromosome 1p for age related cataracts (Iyengar et al., 2004), and has been implicated in both autosomal dominant and recessive congenital as well as age related cataracts, (Jun et al., 2009; Kaul et al., 2010a; Shiels et al., 2008; Sundaresan et al., 2012; Tan et al., 2011; Zhang et al., 2009). Functionally, these results are supported by a cataract risk SNP rs6603883 allele located in a PAX2 binding site within the EPHA2 gene promoter that, when present, downregulates EPHA2 expression (Jun et al., 2009; Ma et al., 2017).

Variants in or near the αA-crystallin gene (CRYAA) are associated with age related cataract, and a p.(F71L) amino acid change identified in patients with age related cataract reduces CRYAA chaperone activity, consistent with a role in age related cataract (Bhagyalaxmi et al., 2010; Bhagyalaxmi et al., 2009; Liao et al., 2014). CRYAA is one of five genes associated with age related nuclear cataract in a large meta-analysis of European and Asian patients, the others being transcription factor SOX2, transmembrane serine protease 5 (TMPRSS5), the lncRNA LINC01412, the BRD4 interacting chromatin remodeling complex associated protein BICRA, and COMM domain containing 10 (COMMD1, inhibits TNF-mediated NF-κB activation). In addition, a number of congenital cataract genes were suggestively but not significantly associated with age related cataracts, as are ITSN2 and MMAB. Further, a cataract associated SNP rs7278468 (T-allele), located in overlapping binding sites for KLF10 and Sp1 within the CRYAA gene promoter, increases KLF10 binding and reduces Sp1 binding thereby downregulating CRYAA protein expression and, potentially, increasing susceptibility to age-related cataract (Ma et al., 2016a; Zhao et al., 2017).

Association of a large number of SNPs near other genes have been reported, although these need confirmation in additional studies. Association of the GSTM1 and the related GSTT1 loci, is inconsistent (Sun et al., 2010; Zuercher et al., 2010). Additionally, polymorphisms in MTHFR, GJA3, GJA8, PARP1, RNF149, OGG1, XPC, ULK4, TLR3, EFNA5, SLC23A1, ESR1, ICA1, PON2, AKR1B1, PTN1, NEIL2, NAT2, WRN, IDO1, TDRD7, GSTP1, CRYAB, SLC11A2, P2RY2, ATM, MIP, B3GNT4, GJA3, ITM2B, OSGEP, SLC7A8, BMP4, SIX6, CYP46A1, KLC1, IGF1R, FTO, MMP2, HSF4, TP53, ASIC2, ACE, SSTR2, MUC16, XRCC1, APOE, LIM2, ZNF350, LSS, and ERCC2, have been reported as associated with age related cataract although additional studies are needed for confirmation of these associations.

In summary, the genetic architecture of inherited congenital and age-related cataracts recapitulates the biology of the lens, with each gene providing insight into the lens structure, function, homeostasis, and development. At this time the list of cataract associated genes is incomplete, with perhaps 40–50% of congenital cataract genes identified even in well characterized populations (Chen et al., 2017), and a lower fraction for age related cataract, with identification of additional genes requiring future genetic studies.

Pathophysiology of Congenital and Age-Related Cataracts

Mechanisms of congenital cataract

α-Crystallin binds only partially denatured crystallins in their aggregation prone molten globule states (Rajaraman et al., 1998; Sathish et al., 2004). Since most mutant crystallins causing congenital cataracts are severely damaged, it is possible that many are not bound by and hence not solubilized by α-crystallin. (Moreau and King, 2012). Even if the destabilized crystallins are bound, it is possible that extensive denaturation of these highly expressed proteins might exhaust the binding capacity of α-crystallin before or soon after birth. This would lead to light scattering HMW aggregates and then denatured and aggregated proteins that would be toxic to the lens cells. However, a recent study of inherited cataracts in mice suggests that mutant forms of αA-, βA2-, or γD-crystallins do not accumulate in the lens but rather result in a proteome imbalance and precipitation of the other non-mutated crystallins (Schmid et al., 2021).

Variable cataracts ranging from total to pulverulent lamellar morphology resulting from a 5-base frameshift insertion (c.119_123dup, c.238insGCGGC, p.C42Afs*63) in CRYGC (Ma et al., 2011; Ren et al., 2000; Scott et al., 1994) show that lens cells can be impaired and the lens microarchitecture destroyed. This mutation encodes an unstable protein in which the first 41 amino acids come from CRYGC followed by 62 novel amino acids. Transgenic mice expressing the mutant protein show progressive degeneration of the fiber cells and eventually gross disruption of lens micro-architecture with large intracellular vacuoles and debris filled lacunae. Similar destructive pathology is seen in other congenital cataract models including mice transgenic for a c.97_357del mutant of CRYBA1 (Ma et al., 2016b).

UPR and Apoptosis in Congenital Cataracts

In a number of mouse models, production of mutant crystallins appears to damage lens cells through induction of the unfolded protein response (UPR) followed by apoptosis (Ikesugi et al., 2006). The UPR is a network of intracellular signaling pathways that senses the fidelity of protein folding in the ER lumen and if necessary adjusts the protein folding capacity to reduce ER stress caused by accumulation of denatured protein in the ER lumen or in extreme cases to induce apoptosis and cell death (Hetz et al., 2020). In the absence of unfolded proteins BiP (HSPA5 HSPA5, GRP78) and perhaps other mediators binds to at least three major ER sensors: IRE1, ATF6, and PERK (EIF2AK3), keeping them inactive. Bip binds unfolded proteins preferentially, causing it to dissociate from the three sensors, so that they then initiate the UPR. Under mild stress the UPR decreases protein synthesis, upregulates endoplasmic reticulum associated degradation proteins (ERAD), and increases chaperone levels to reduce stress (Sovolyova et al., 2014). It is of note that even the early UPR might induce accumulation of p26, inhibiting denucleation of the cortical fiber cells and leading to opacity (Lyu et al., 2016). However, if the UPR fails to achieve homeostasis it induces apoptosis through both the intrinsic and mitochondrial-mediated apoptotic pathways (Gupta et al., 2010; Lai et al., 2007; Rasheva and Domingos, 2009; Szegezdi et al., 2008) as well as PERK regulation of gene expression. The apoptotic pathways include induction transcription of specific genes such as XBP1 and IRE1 by ATF6 (Gupta et al., 2012), after which IRE1 cleaves XBP1, activating it and inducing transcription of a broad array of downstream mediators including nucleoporin 58 (NUP58) (Gorman et al., 2012) and DNA-damage-inducible transcript 3 (DDIT3), all of which induce apoptosis to produce the lens pathology observed in the congenital cataract models described above.

The UPR and cellular apoptosis leading to destruction of the lens microarchitecture with cellular disarray and vacuoles filled with proteinaceous debris has been shown to be at least one of the pathogenic mechanisms in congenital cataracts, including the p.C42Afs*63 mutant CRYGC transgenic mouse cataracts mentioned above (Ma et al., 2011). Other examples include the knock-in p.Arg49Cys CRYAA mouse (Andley and Goldman, 2015), mice expressing p.Ser50Pro and p.Gly22Arg GJA8 mutations (Alapure et al., 2012), mice transgenic for the p.Ile33_Ala119del mutant βA3/A1-crystallin protein (Ma et al., 2016b), a p.Asp47Ala Cx50 mutant (Berthoud et al., 2016), and a p.Ser73Pro mutation in GJA8 in cultured lens epithelial cells (Li et al., 2019). Additionally there is strong evidence implicating the UPR in spontaneous mouse cataract models, examples of which include a MIP p.Ala51Pro mutation (Zhou et al., 2016). Thus, at least some and perhaps most congenital cataracts involve induction of the UPR with subsequent apoptosis of cortical fiber cells resulting in destruction of the lens microarchitecture. In contrast, light scattering by HMW protein aggregates appears to be the main process for age-related cataract, although in some cases they might share a final common pathway (Fig. 3).

Figure 3.

Figure 3.

Dual pathways for inherited cataracts. Severe mutations shown on the left would induce the UPR and apoptosis and be more likely to cause highly penetrant Mendelian congenital cataracts. Mild variants would increase susceptibility to environmental insults, being bound by α-crystallin and leading over time to multifactorial age-related cataracts. Black arrows: demonstrated pathways, gray arrows: likely pathways.

Chaperone Binding and HMW Aggregates in Age Related Cataracts

As mentioned above most age related cataracts represent a final common end point of a long course of crystallins slowly undergoing denaturation through the combined effects of environmental insults, destabilizing variations in their sequence, and loss of the protective environment of the lens fiber cells including insults to the lens epithelia (Hejtmancik and Kantorow, 2004). α-Crystallins act as chaperones to bind and solubilize partially denatured proteins and delay HMW formation and light scattering (Haslbeck et al., 2015), protecting the lens from their toxic effects (Horwitz, 2003). Datiles et al. have demonstrated this process by following levels of free and HMW-complexed α-crystallin in human cataract patients using dynamic light scattering (Datiles et al., 2008). They found a six-fold decrease in free α-crystallin with age, even in clear lenses, and an additional ten-fold decrease in age-related cataract lenses as the AREDS nuclear cataract grade increases to two or above. At this point free α-crystallin is completely consumed leaving large light scattering HMW complexes but no free α-crystallin for future buffering of damaged crystallins, with the lens microarchitecture mostly intact. In some of these patients as additional protein is denatured but not bound by CRYAA the UPR might be activated by the toxic aggregates, consistent with reports that the UPR is induced in age related cataract (Yang et al., 2015) as well as a slowly progressing opacity over time leading to accelerated opacification over weeks or months described clinically in some individuals.

In summary, the pathogenic mechanisms of inherited cataracts generally can be divided into two different, but perhaps overlapping, pathways for which cataract is the common endpoint. Some, if not most, congenital cataracts are caused by mutations that severely destabilize crystallins or disrupt lens homeostasis, often through activation of the UPR and subsequent apoptosis. Age-related and progressive juvenile cataracts accumulate damage to βγ-crystallins that are then bound by α-crystallin through its chaperone ability until it is exhausted. The α-crystallin complexes increase in size, forming HMW aggregates capable of light scattering, and in some cases precipitate and damage the lens microarchitecture as in the congenital cataract pathway. It is also possible that some of the aggregates eventually form amyloid-like fibrils that might also damage the lens (Meehan et al., 2004; Xi et al., 2015). While the dual pathway concept will certainly be refined and extended over time, involvement of two pathways for congenital and age-related cataracts seems likely given the current state of our knowledge.

Highlights:

  1. The spectrum of mutations causing and contributing to inherited cataracts reflect important biological processes in the lens.

  2. There are two basic pathways by which inherited cataracts occur.

  3. Congenital cataracts tend to result from severe mutations that cause immediate denaturation and precipitation of crystallins or damage to homeostatic systems in the lens.

  4. At least some congenital cataracts involve disruption of the lens microarchitecture with cell death and disarray, often as a result of induction of the UPR and apoptosis.

  5. Age-related cataracts result from multifactorial causes including environmental stresses acting on inherited predispositions resulting from mildly destabilized crystallins or homeostatic systems.

  6. As crystallins are partially destabilized they are bound by α-crystallins, eventually forming HMW aggregates and scattering light.

  7. While these are distinct pathways they might overlap at a number of points, at least in some cases.

Footnotes

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