Biology of Inherited Cataracts and Opportunities for Treatment

Abstract

Cataract, the clinical correlate of opacity or light scattering in the eye lens, is usually caused by the presence of high-molecular-weight (HMW) protein aggregates or disruption of the lens microarchitecture. In general, genes involved in inherited cataracts reflect important processes and pathways in the lens including lens crystallins, connexins, growth factors, membrane proteins, intermediate filament proteins, and chaperones. Usually, mutations causing severe damage to proteins cause congenital cataracts, while milder variants increasing susceptibility to environmental insults are associated with age-related cataracts. These may have different pathogenic mechanisms: Congenital cataracts induce the unfolded protein response and apoptosis. By contrast, denatured crystallins in age-related cataracts are bound by α-crystallin and form light-scattering HMW aggregates. New therapeutic approaches to age-related cataracts use chemical chaperones to solubilize HMW aggregates, while attempts are being made to regenerate lenses using endogenous stem cells to treat congenital cataracts.

Keywords: cataract; crystallin; genetics; lens.

Figure 1.

Possible pathways for inherited cataracts. Severe mutations would be more likely to cause highly penetrant Mendelian congenital cataracts, while mild changes would be likely to increase susceptibility to environmental insults and lead to multifactorial age-related cataracts. Black arrows show demonstrated pathways and gray arrows show likely pathways.