arranged by date

Sushruta in 600 B.C. introduced extraocular expulsion of lens material. Acta Opht. 2013;92(2):194-197.  

First surgical procedure recounted of cataract surgery from Sanskrit Sushruta medical textbook BC 500. 

Stratford SJ. On the varieties of cataract; their causes, formation, and cure. The London Medical and Physical Journal 1828. 

Previous accounts of individual cases/surgeries, but this is the first comprehensive account. He accounts the characteristics of the eye, and where cataracts occur. He accounts the white cloudy color, and the differences between age-related and congenital cataracts. Age-related being hard when extracted, but congenital in infants holding liquid. He states that cataracts can occur from acute or chronic inflammation of the lens and its membrane capsule, an eye injury, a rupture of the blood vessels, or a rupture of the capsule which allows the lens to move. He also states that each case requires a different surgical method.

Morner, Th Carl. Examinations of protein substances in the easily reflective media of the eye. Journal of Physiological Chemistry 1894;18(1):61-106.

This textbook is completely inaccessible through the library or anywhere because of how old it is and it being in Swedish! However, Morner has been cited as isolating the alpha, beta, and gamma crystallin from bovine lens. 

Hubbel AA. Samuel Sharp, the First Surgeon to make the Corneal Incision in Cataract Extraction with a Single Knife. Medical Library and Historical Journal. 1904 Oct; 2(4): 242.1–268.

Intraocular lens extraction involves breaking the zonular lens fibers.

Kelman CD. Phaco-Emulsification and Aspiration. American Journal of Ophthalmology. 1969;67(4):464-477. doi:10.1016/0002-9394(69)94252-4.

Report of the first use of phacoemulsification surgery for cataract removal.

Ingolia TD, Craig EA. Four small Drosophila heat shock proteins are related to each other and to mammalian alpha-crystallin. Proc Natl Acad Sci USA 1982;79(7):2360–2364. 

The sequence was found for the protein coding region of the four heat shock proteins and compared to a-crystallin, proving to have 39 of the 76 amino acids similar to three of the proteins, and 53 amino acids similar to the other protein. This identified an important domain with its function yet to be determined, but proposed to be related to aggregation of the lens, possibly protecting DNA. 

Shalini VK, Luthra M, Srinivas L, Rao SH, Basti S, Reddy M, Balasubramanian D. Oxidative damage to the eye lens caused by cigarette smoke and fuel smoke condensates. Indian Journal of Biochemistry & Biophysics, 31 Jul 1994, 31(4):261-266

The inhalation of cigarette smoke causes the accumulation of oxidative damage in the lens, as the crystallin proteins are not regenerated and result in opacities.

Hawkins JW. Confirmation of assignment of the human alpha 1-crystallin gene (CRYA1) to chromosome 21 with regional localization to q22.3. Human genetics 1987;76(4):375-80

Authors used an oligonucleotide with similar sequence to α-crystallin gene to confirm and localize the gene to 21q22.3. 

Horwitz J. α-Crystallin can function as a molecular chaperone. Proc. Nadl. Acad. Sci. USA 1992;98:10449-10453.

α-crystallin suppresses aggregation of b and g crystallins in the eye. Shown in vivo. 

Horwitz J. Evidence that a-crystallin prevents non-specific protein aggregation in the intact eye lens. Biochimica et Biophysica Acta 1995;1245(3):439-447. 

Knocking out α-crystallin when heat is induced results in aggregation, but with a-crystallin complexes to the aggregates creates a soluble fraction, preventing opacifications. 

Sharma KK, Kumar RS, Kumar GS, Quinn PT. Synthesis and Characterization of a Peptide Identified as a Functional Element in αA-crystallin. Journal of Biological Chemistry. 2000;275(6):3767-3771. doi:10.1074/jbc.275.6.3767.

Defined the substrate binding sites of αA-crystallin.

Mackay D, Andley U, Shiels A. Cell death triggered by a novel mutation in the alphaA-crystallin gene underlies autosomal dominant cataract linked to chromosome 21q. Eur J Hum Genet. 2003;11:784–793.

Authors found the first mutation which lies outside of the sHSP domain of the gene causing autosomal dominant cataracts. This raises the possibility of incorrect disulfide bridge formation in quaternary structure of the protein. The mutation was found to both increase apoptosis and to be cytotoxic to the cell. 

Biswas A, and Das K.P.. Role of ATP on the Interaction of α-Crystallin with Its Substrates and Its Implications for the Molecular Chaperone Function. Journal of Biological Chemistry, 279, 41, 42648–42657 (2004).

Binding of ATP increases chaperone function of α-Crystallin and creates a tighter substrate binding complex.

Bloemendal H, Jong WD, Jaenicke R, Lubsen NH, Slingsby C, Tardieu A. Ageing and vision: structure, stability and function of lens crystallins. Progress in Biophysics and Molecular Biology. 2004;86(3):407-485. doi:10.1016/j.pbiomolbio.2003.11.012.

Structure, interactions, and stability of the crystallin proteins are associated with the transparency of the lens.

Augusteyn RC. α-crystallin: a review of its structure and function. Clinical and Experimental Optometry. 2004;87(6):356-366. doi:10.1111/j.1444-0938.2004.tb03095.x.

α-crystallin has been investigated to allow for substrate interaction through subunit exchange from the parent oligomer.

Basha E, Friedrich KL, Vierling E. The N-terminal Arm of Small Heat Shock Proteins Is Important for Both Chaperone Activity and Substrate Specificity. Journal of Biological Chemistry. 2006;281(52):39943-39952. doi:10.1074/jbc.m607677200.

Variable N-termini of heat shock proteins contribute to their ability to bind different substrates.

Ikesugi K, Yamamoto R, Mulhern ML, Shinohara T. Role of the unfolded protein response (UPR) in cataract formation. Experimental Eye Research. 2006;83(3):508-516.

The unfolded protein response is most likely a large player in cataract formation due to the addition of endoplasmic stressors resulting in a higher number of cell deaths in lens epithelial cells, increasing the activation of caspase. The presence of reactive oxygen species caused apoptosis depending on the duration of exposure of the cells. This can affect the characteristics of different cataracts.

Lindbland BE, Hakansson N, Philipson B, Wolk A. Alcohol Consumption and Risk of Cataract Extraction. AAO Journal Ophtha. 2007;114(4):680-685. DOI:

Increasing daily alcohol intake increase risk of cataracts in women.

Vembar SS, Brodsky JL. One step at a time: endoplasmic reticulum-associated degradation. Nature Reviews Molecular Cell Biology. 2008;9(12):944-957. doi:10.1038/nrm2546.

The endoplasmic reticulum associated degradation pathway is responsible for the target of substrates for their degradation in the ubiquitin pathway via molecular chaperones.

Hejtmancik JF. Congenital cataracts and their molecular genetics. Seminars in Cell and Developmental Bio. 2008;19(2):134-139.

Autosomal recessive αA-crystallin results from a truncated tryptophan in the beginning of the protein sequence, while autosomal dominant inheritance is resulting from missense arginine mutations. The author also outlines all of the known mutations at the time and how they are classified in the zones of the lens. Lens transparency results from appropriate architecture of lens cells and tight packing of their proteins, resulting in constant refractive index over distances approximating the wavelength of light.

Andley U. Effects of α-Crystallin on Lens Cell Function and Cataract Pathology. Current Molecular Medicine. 2009;9(7):887-892. doi:10.2174/156652409789105598.

Changes in a-crystallin are responsible for lens pathology and the incidence of cataracts.

Karmakar S, Das KP. Identification of Histidine Residues Involved in Zn2 Binding to αA- and αB-Crystallin by Chemical Modification and MALDI TOF Mass Spectrometry. The Protein Journal. 2012;31(7):623-640. doi:10.1007/s10930-012-9439-0.

H79, H107 and H115 of αA-crystallin and H104, H111 and H119 of aB-crystallin are involved in binding of Zn2+.

Laurie KJ, Dave A, Straga T, et al. Identification of a Novel Oligomerization Disrupting Mutation inCRYΑAAssociated with Congenital Cataract in a South Australian Family. Human Mutation. 2013;34(3):435-438. doi:10.1002/humu.22260.

This heterozygous mutation reduces the number of oligomers and the chaperone function of a-Crystallin.

Linetsky M, Raghavan CT, Johar K, et al. UVA Light-excited Kynurenines Oxidize Ascorbate and Modify Lens Proteins through the Formation of Advanced Glycation End Products. Journal of Biological Chemistry. 2014;289(24):17111-17123. doi:10.1074/jbc.m114.554410.

UV radiation increases covalent modification of crystallin proteins, positively associated with cataracts.

Makley LN, McMenimen KA, DeVree BT, et al. Pharmacological chaperone for α-crystallin partially restores transparency in cataract models. Science 2015;350(6261):674–677.

By investigating the thermal stability of different chaperone molecules, one compound was found to bind to CRYAA and CRYAB to increase the thermal stability and reversing protein aggregates in mice that had mutated forms of the genes. 

Yang J, Zhou S, Gu J, Guo M, Xia H, Liu Y. UPR Activation and the Down–Regulation of α-Crystallin in Human High Myopia-Related Cataract Lens Epithelium. Plos One. 2015;10(9). doi:10.1371/journal.pone.0137582.

ER stress responses are an indicator of reduced α-Crystallin expression.

Sunkireddy P, Jha SN, Kanwar JR, Yadav SC. Natural antioxidant biomolecules promises future nanomedicine based therapy for cataract. Colloids and Surfaces B: Biointerfaces. 2013;112:554-562. doi:10.1016/j.colsurfb.2013.07.068.

Current and future directions of drug delivery to prevent and treat cataracts are discussed, mostly by the ability to decrease reactive oxygen species.

Panda AK, Nandi SK, Chakraborty A, Nagaraj RH, Biswas A. Differential role of arginine mutations on the structure and functions of α-crystallin. Biochem Biophys Acta. 2016;1860(1 Pt B):199–210.

Six of the congenital cataract mutations are from the substitution of an arginine residue, indicating that these residues are important in the chaperon function of α-crystallin A. Mutations from other residues TO arginine additionally actually aids in lens transparency, rather than hindering it, suggesting that positive residues are beneficial. In previous studies substitution with lysine preserved function. 

Hejtmancik JF, Riazuddin SA, McGreal R, Liu W, Cvekl A, Shiels A. Lens Biology and Biochemistry. Prog Mol Biol Transl Sci. 2015;134:169‐201. doi:10.1016/bs.pmbts.2015.04.007

Lens transparency upkeep is a consolidation of the lens cells, microstructures, and proteins.

Tjondro HC, Xi Y-B, Chen X-J, Su J-T, Yan Y-B. Membrane insertion of αA-crystallin is oligomer-size dependent. Biochemical and Biophysical Research Communications. 2016;473(1):1-7. doi:10.1016/j.bbrc.2016.03.033.

Increasing the size of the protein can increase the hydrophobic residues and its membrane binding ability.

Davis G. The Evolution of Cataract Surgery. Mo Med. 2016 Jan-Feb; 113(1): 58–62.

The history of cataract surgery from couching to present day extraction.

Hetz C, Papa FR. The Unfolded Protein Response and Cell Fate Control. Molecular Cell. 2018. 69 (2): 169–181. doi:10.1016/j.molcel.2017.06.017

Endoplasmic reticulum stressors trigger the unfolded protein response which can trigger apoptosis.

Phadte AS, Santhoshkumar P, Sharma KK. Characterization of an N-terminal mutant of αA-crystallin αA-R21Q associated with congenital cataract. Experimental Eye Research 2019;182:10-19. 

The mutant increases surface hydrophobicity and actually exhibits increased chaperone activity while increasing affinity to proteins αA-crystallin is unfolding. This highlights the importance of this residue in the protein’s mechanism, and that this mutation actually results in an enhanced function. 

Kaiser C.J.O., Peters C., Schmid P.W.N. et al. The structure and oxidation of the eye lens chaperone αA-crystallin. Nat Struct Mol Biol 26, 1141–1150 (2019).

The crystal structure of the 16-mer αA-crystallin was identified and characterized.

OMIM entry *123580 CRYAA

Accounts the history and mutations present in the gene.

Cataracts. American Ophthalmic Association.

Overview and causes of cataracts.

Heiting G. How Carotenoids Keep your Eyes Healthy. All About Vision.

Carotenoids found in leafy green vegetables act as antioxidants to fight oxidative stress. The red pigment directly opposes that of blue light from damaging our eyes.

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