The two stress responses of the unfolding cytoplasmic proteins and endoplasmic reticulum proteins both upregulate chaperone proteins. As the crystallin proteins are expressed in such high concentrations, mutations of β- and 𝛾-crystallins resulting in higher misfolding would cause them to aggregate quicker than α-crystallin could take care of them.
α-crystallin has a finite capacity of chaperone function, decreasing and becoming less efficacious over time. In age-related cataracts, this is the primary reason for cataract formation. Post-translational modifications as well as the formation of disulfide bridges over time inhibits the function of α-crystallin1. The can include the addition of an phosphorylation, amidation, and glycation as outlined in Figure 1.
In congenital cataracts, inherent mutations in genetic code cause alterations to the hydrophobicity, chaperone activity, subunit interactions, and substrate binding of α-crystallin. The several mutations involving change of a hydrophobic amino acid from arginine would suggest that the charge on the surface of α-crystallin is critical for chaperone function and stability3.
In recessive cases of αA-crystallin, similar to anemia, half of the proteins are able to function normally while the other half either form aggregates themselves or are unable to function. However, dominant cases tend to actually damage the cell or the proteins they are supposed to stabilize3.
Endoplasmic reticulum stressors are able to induce apoptosis in the lens epithelial cells via the unfolded protein response. According to Yang, the reduced expression of α-crystallin is shown in mouse models with cataracts with several ER stress response pathways activated. It is not known whether reduced expression of α-crystallin comes first and triggers the unfolded protein response, or whether it’s synthesis is decreased as a result4.
αB-crystallin expression is triggered by temperature and osmotic stress to the cells, while αA-crystallin is not. This signifies that although they are both chaperones, the two subunits serve somewhat different functions to the lens.
β𝛾 crystallin mutations result in a lack of soluble protein, eventually causing opacities1.
Some mutations affect the solubility of αA-crystallin. It has been shown that increasing oligomeric size can increase the hydrophobicity of the protein, causing it to be incorporated into the membrane and prevent its chaperone function5. R116C, R116H, and Y118D are cataract-causing mutations that affect the membrane binding ability of αA-crystallin. Heat-treated cells showed this increase, indicating that membrane binding may be a preference during stress responses due to aging, although it is unclear whether this specifically affects chaperone function. This is only present in age-related cataracts.
An R21Q mutant of CRYAA found to be cataract-causing in a family. The increased surface hydrophobicity of this mutant increased its membrane association as well as chaperone activity6. Although this sounds like a good thing, this mutation alters the quaternary structure of a-crystallin into oligomers and therefore causes cataracts due to the disruption of light refraction7.
Although most mutations occur in the α-crystallin domain, the N and C terminus are still very much important for the activity of the protein. Whether they pertain to oligomer formation, subunit binding, substrate interaction, all the mutations documented alter the chaperone activity or solubility of α-crystallin and cause cataracts besides the W9X mutation which was autosomal recessive8.
- Bloemendal 2004
- Andley 2009
- Hejtmancik 2008
- Yang 2015
- Tjondro 2016
- Phadte 2018
- Laurie 2012
- OMIM entry 123580 CRYAA