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The human W42R ?D-crystallin mutant structure provides a link between congenital and age-related cataracts.

ABSTRACT: Some mutants of human ?D-crystallin are closely linked to congenital cataracts, although the detailed molecular mechanisms of mutant-associated cataract formation are generally not known. Here we report on a recently discovered ?D-crystallin mutant (W42R) that has been linked to autosomal dominant, congenital cataracts in a Chinese family. The mutant protein is much less soluble and stable than wild-type ?D-crystallin. We solved the crystal structure of W42R at 1.7 ? resolution, which revealed only minor differences from the wild-type structure. Interestingly, the W42R variant is highly susceptible to protease digestion, suggesting the presence of a small population of partially unfolded protein. This partially unfolded species was confirmed and quantified by NMR spectroscopy. Hydrogen/deuterium exchange experiments revealed chemical exchange between the folded and unfolded species. Exposure of wild-type ?D-crystallin to UV caused damage to the N-terminal domain of the protein, resulting in very similar proteolytic susceptibility as observed for the W42R mutant. Altogether, our combined data allowed us to propose a model for W42R pathogenesis, with the W42R mutant serving as a mimic for photodamaged ?D-crystallin involved in age-related cataract.

SUBMITTER: Ji F

PROVIDER: S-EPMC3537076 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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The human W42R γD-crystallin mutant structure provides a link between congenital and age-related cataracts.

Ji Fangling F Jung Jinwon J Koharudin Leonardus M I LM Gronenborn Angela M AM

The Journal of biological chemistry 20121102 1

Some mutants of human γD-crystallin are closely linked to congenital cataracts, although the detailed molecular mechanisms of mutant-associated cataract formation are generally not known. Here we report on a recently discovered γD-crystallin mutant (W42R) that has been linked to autosomal dominant, congenital cataracts in a Chinese family. The mutant protein is much less soluble and stable than wild-type γD-crystallin. We solved the crystal structure of W42R at 1.7 Å resolution, which revealed o ...[more]

PMID: 23124202

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Project description:Purpose:To identify mutations in crystallin genes in Chinese families with congenital cataracts. Methods:Forty-two unrelated families with non-syndromic congenital cataracts were enrolled in this study. The coding exons and adjacent intronic regions of crystallin genes, including CRYAA, CRYAB, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD and CRYGS, were analyzed with Sanger sequencing. Novel variants were further evaluated in 112 ethnically matched controls. To confirm the novel mutations, short tandem repeat (STR) haplotypes were constructed to check the cosegregation with congenital cataract. The pathogenic potential of the novel mutations were assessed using bioinformatics tools, including Sorting Intolerant From Tolerant v5.1.1 (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Human Splicing Finder. The pathogenicity of all the mutations was evaluated according to the guidelines of the American College of Medical Genetics (ACMG) and InterVar software. Results:Seven previously reported mutations in crystallin genes identified in ten unrelated families were associated with the congenital nuclear cataracts. Four novel mutations in crystallin genes, including c.35G>T (p.R12L) in CRYAA, c.463C>A (p.Q155K) in CRYBB2, IVS1 c.10-1G>A in CRYGC, and c.346delT (p.F116Sfsx29) in CRYGD, were identified in four unrelated families with congenital cataracts. These mutations cosegregated with all affected individuals in each family were not observed in the unaffected family members or in the 112 unrelated controls. All four novel mutations were categorized as disease "likely pathogenic" except IVS1 c.10-1G>A in CRYGC "pathogenic" using InterVar software in accordance with the ACMG standard. Mutations in crystallin genes were responsible for 33.33% of the Chinese families with congenital cataracts in this cohort. Conclusions:In this study, we identified four novel mutations in crystallin genes in Chinese families with congenital cataracts. The results expand the mutational spectrum of crystallin genes, which may be helpful for the molecular diagnosis of congenital cataracts in the era of precision medicine.

Project description:BackgroundWith the development of the economy, socioeconomic factors, such as inequalities in the status of regional economies and the subsequent effects on health systems, have influenced the status of health. We explored the association between age-related cataracts and socioeconomic indicators, including the regional economy, health systems, and energy industries.MethodsThis was a prospective, multicenter, Chinese population-based, cross-sectional study. A total of 830 participants from seven centers were enrolled. Data on the best-corrected visual acuity (BCVA), Lens Opacities Classification System III (LOCS III) score, Visual Function Index-14 (VF-14) score, total and subscale scores of the 25-item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), per capita disposable income (PCDI), medical resource-related indicators, and investments in the energy industry were obtained. Associations among these parameters were analyzed.ResultsThe PCDI ranking was correlated with the VF-14 score (R = -0.426, P < 0.01), total score of NEI-VFQ-25 (r = -0.500, P < 0.01), and BCVA (r = 0.278, P < 0.01). The number of health agencies (r1 = 0.267, r2 = -0.303, r3 = -0.291,), practicing or assistant practicing doctors (r1 = -0.283, r2 = 0.427, r3 = 0.502,), registered nurses (r1 = -0.289, r2 = 0.409, r3 = 0.469, P < 0.01), and health technicians (r1 = -0.278, r2 = 0.426, r3 = 0.500, P < 0.01) per 10,000 of the population was each correlated with the BCVA, VF-14 score, and total score of NEI-VFQ-25, respectively. Health expenditure per capita was correlated with the VF-14 score (r = 0.287, P < 0.01) and total score of NEI-VFQ-25 (r = 0.459, P < 0.01). The LOCS III P score was correlated with investments in the energy industry (r = 0.485, P < 0.001).ConclusionsPatients in higher economic regions with greater medical resources show a greater demand to undergo cataract surgery at a better subjective and objective visual function. The energy industry has a significant effect on cataracts, especially the posterior subcapsular cataract, and thus more attention should be paid to people in regions with abundant energy industries.

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The human W42R ?D-crystallin mutant structure provides a link between congenital and age-related cataracts.

Publications

The human W42R γD-crystallin mutant structure provides a link between congenital and age-related cataracts.

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