Research articleMutations and mechanisms in congenital and age-related cataracts
Introduction
Cataract can be defined broadly as any opacity of the crystalline lens. This has been shown to happen whenever the refractive index of the lens varies significantly over distances approximating the wavelength of the transmitted light (Benedek, 1971, Delaye and Tardieu, 1983). This variation in the refractive index can occur as a result of a variety of changes, including alterations of lens cell structure, lens proteins or a combination of both (Hejtmancik et al., 2001). Alterations to the geometric order of the lens and its membranes can amplify these effects and this can increase light scattering. Congenital cataracts are often associated with breakdown of the lens micro-architecture. Vacuoles can form and cause large fluctuations in optical density with concomitant light scattering. In contrast, age related cataracts are often characterized by light scattering and opacity resulting from the buildup of high molecular weight protein aggregates (HMW), generally 1000 Å or more in size. This can also disrupt the short-range ordered packing of lens crystallins, which is critical for maintaining the crystallins in a homogeneous phase, with disastrous consequences for lens transparency as they compose over 90% of soluble lens proteins. However, while formation of large protein complexes might be a common end point in many cataracts, it is important to remember that reduced and disrupted refractive properties in the lens do not result from protein aggregation and precipitation in all cases. Mutations in BFSP2 were first identified in myopic patients in whom opacification of the lens sutures was only found upon closer examination (Zhang et al., 2004). In addition, age related cataract might not be a simple function of protein precipitation, as shown by the existence of multilamellar bodies in age related cataract (Costello et al., 2012). Finally, the two mechanisms of crystallin aggregation and micro-architectural disruption are not exclusive, as the proper lens cell environment is important for the maintenance of lens crystallin structure and existence in a homogeneous phase.
Cataracts can be defined by age at onset, although the boundaries between different types of cataract are approximate. A cataract is termed congenital or infantile if it is observed within the first year of life. If onset occurs within the first decade of life cataract is termed juvenile and a cataract with an onset later but before the age of 45 years is called presenile, with senile or age-related cataracts generally occurring after 50 or perhaps 60 years of age. The situation is complicated because subtle cataracts, which can easily be asymptomatic, might not be brought to clinical attention for years after their onset. In addition, a cataract’s age of onset does not imply a particular etiology. About 8.3–25% of congenital cataracts are hereditary (Francois, 1982, Haargaard et al., 2005, Merin, 1991) with the remainder generally caused by an intrauterine infection (e.g. rubella) or other prenatal insult. Secondary cataracts such as those occurring as part of a systemic disease life (e.g., retinitis pigmentosa) may be delayed as late as the second or third decade of life. However, the age of onset of a cataract serves as a useful metric with which to group cataracts, and it would seem logical that, while cataracts within each group will certainly have a variety of mutations in different genes affecting specific cellular processes they might share some similarities in their general pathogenic mechanisms, as detailed in the following paragraph.
We and others have suggested that when mutations in crystallins or other lens proteins are sufficient in and of themselves to cause protein aggregation rapidly and directly, they usually result in congenital cataract. In contrast, if they are benign enough merely to increase susceptibility to environmental insults, including hyperglycemic and dietary (Weikel et al., 2014), ultraviolet light (Taylor et al., 1988), or oxidative (Brennan et al., 2012, Truscott, 2005) damage, they would tend to contribute to age related cataract (Hejtmancik and Smaoui, 2003, Shiels and Hejtmancik, 2007) by exacerbating the accumulation of damage seen to long lived lens proteins with aging (Truscott and Friedrich, 2016). Consistent with these proposed mechanisms, hereditary congenital cataracts are most often transmitted in a highly penetrant Mendelian fashion, and cataracts with a later origin, including progressive and age-related cataracts, are often multifactorial, with contributions from multiple genes providing from 35% to as much as 58% of the risk (McCarty and Taylor, 2001) as well as environmental insults. Although this makes them significantly less amenable to genetic and biochemical study than congenital cataracts, inroads are beginning to be made into their genetic etiologies and in some cases their molecular mechanisms.
Section snippets
Inherited congenital cataract mutations
Isolated or primary congenital cataracts currently have been mapped to at least 44 genetic loci (Table 1), exhibiting a wide variety of lens opacity morphologies including, nuclear, lamellar, sutural, polar and total (Merin, 1991). While the causative genes have not been identified at 11 of these loci the genes that have been discovered tend to fall into a number of functional groups that identify critical biological processes in the eye lens. Of the cataract families for whom the mutant gene
Age-related cataract variants and loci
Age-related cataracts (ARC) also have a genetic component, although the sequence variations contributing to ARC tend to increase the risk of disease against a background of environmental insults to which all individuals are exposed presumably by making individuals having the variation more vulnerable to a variety environmental insults accumulated over many years (McCarty and Taylor, 2001, Shiels and Hejtmancik, 2010). Although often occurring in a mixed pattern when advanced, age-related
Acknowledgements
This work was supported in part by National Institutes of Health/National Eye Institute (NIH/NEI) grants EY012284 and EY023549 (to AS) and EY02687 (Core Grant for Vision research), and by an unrestricted grant to the Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness (RPB).
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