Cataract-causing mutations L45P and Y46D promote γC-crystallin aggregation by disturbing hydrogen bonds network in the second Greek key motif

Fu, Chenxi; Xu, Junjie; Jia, Zhaobao; Yao, Ke; Chen, Xiangjun

doi:10.1016/j.ijbiomac.2020.11.158

Cited by 16 publications

(10 citation statements)

References 45 publications

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“…Cataracts, which can be defined as an opacity of the crystalline lens, are produced by the misfolding and aggregation of proteins [ 1 ] that adversely affect the transmission of light on the retina. Because genetic mutations and environmental stress can affect the protein-folding process in different ways, the molecular mechanisms of how disruptions to the crystalline lens protein stability, solubility, and interactions [ 27 , 28 , 29 ] result in cataracts remain unclear. Lens proteins undergo various alterations, including oxidative, osmotic, and other stresses [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Polygenic Risk Score Improves Cataract Prediction in East Asian Population

et al. 2022

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Cataracts, characterized by crystalline lens opacities in human eyes, is the leading cause of blindness globally. Due to its multifactorial complexity, the molecular mechanisms remain poorly understood. Larger cohorts of genome-wide association studies (GWAS) are needed to investigate cataracts’ genetic basis. In this study, a GWAS was performed on the largest Han population to date, analyzing a total of 7079 patients and 13,256 controls from the Taiwan Biobank (TWB) 2.0 cohort. Two cataract-associated SNPs with an adjustment of p < 1 × 10−7 in the older groups and nine SNPs with an adjustment of p < 1 × 10−6 in the younger group were identified. Except for the reported AGMO in animal models, most variations, including rs74774546 in GJA1 and rs237885 in OXTR, were not identified before this study. Furthermore, a polygenic risk score (PRS) was created for the young and old populations to identify high-risk cataract individuals, with areas under the receiver operating curve (AUROCs) of 0.829 and 0.785, respectively, after covariate adjustments. Younger individuals had 17.45 times the risk while older people had 10.97 times the risk when comparing individuals in the highest and lowest PRS quantiles. Validation analysis on an independent TWB1.0 cohort revealed AUROCs of 0.744 and 0.659.

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Section: Discussionmentioning

confidence: 99%

Polygenic Risk Score Improves Cataract Prediction in East Asian Population

et al. 2022

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“…The path-length was 0.5 mm, and the range of scanning wavelength was from 200 to 250 nm. The intrinsic fluorescence and the extrinsic ANS fluorescence were measured using a F-4600 fluorescence spectrophotometer (Hitachi, Tokyo, Japan) using previously described methods and parameters ( Yang et al, 2020 ; Fu et al, 2021 ; Liu et al, 2022 ). The excitation wavelength for intrinsic fluorescence was 280 nm for Trp and Tyr fluorescence and 295 nm for Trp fluorescence.…”

Section: Methodsmentioning

confidence: 99%

Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability

Ren

Zhang

et al. 2022

Front. Mol. Biosci.

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Cataract, opacity of the eye lens, is the leading cause of visual impairment worldwide. The crucial pathogenic factors that cause cataract are misfolding and aggregation of crystallin protein. βB1‐crystallin, which is the most abundant water‐soluble protein in mammalian lens, is essential for lens transparency. A previous study identified the missense mutation βB1‐S93R being responsible for congenital cataract. However, the exact pathogenic mechanism causing cataract remains unclear. The S93 residue, which is located at the first Greek‐key motif of βB1‐crystallin, is highly conserved, and its substitution to Arginine severely impaired hydrogen bonds and structural conformation, which were evaluated via Molecular Dynamic Simulation. The βB1‐S93R was also found to be prone to aggregation in both human cell lines and Escherichia coli. Then, we isolated the βB1‐S93R variant from inclusion bodies by protein renaturation. The βB1-S93R mutation exposed more hydrophobic residues, and the looser structural mutation was prone to aggregation. Furthermore, the S93R mutation reduced the structural stability of βB1-crystallin when incubated at physiological temperature and made it more sensitive to environmental stress, such as UV irradiation or oxidative stress. We also constructed a βB1-S93R cellular model and discovered that βB1-S93R was more sensitive to environmental stress, causing not only aggregate formation but also cellular apoptosis and impaired cellular viability. All of the results indicated that lower solubility and structural stability, sensitivity to environmental stress, vulnerability to aggregation, and impaired cellular viability of βB1-S93R might be involved in cataract development.

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“…By now more than thirty one and fifteen cataract associated single nucleotide polymorphisms (SNPs) and mutations have been described in mouse and human γ-crystallin, respectively (23), and the list keeps growing (24). In the end, the pharmacological challenge is to find ways to prevent the formation of the light scattering aggregates.…”

Section: Introductionmentioning

confidence: 99%

“…When such stress is applied, the N-terminal domain tends to unfold first ( 21 ), a process that is enhanced with certain cataract-prone mutations, such as the W43R mutation ( 22 ). By now, more than 31 and 15 cataract-associated SNPs and mutations have been described in mouse and human γ-crystallin, respectively ( 23 ), and the list keeps growing ( 24 ). In the end, the pharmacological challenge is to find ways to prevent the formation of the light scattering aggregates.…”

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confidence: 99%