The lens of the eye has long been considered as a radiosensitive tissue, but recent research has suggested that the radiosensitivity is even greater than previously thought. The 2012 recommendation of the International Commission on Radiological Protection (ICRP) to substantially reduce the annual occupational equivalent dose limit for the ocular lens has now been adopted in the European Union and is under consideration around the rest of the world. However, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological, mechanistic evidence at doses <2Gy. This paper aims to present a review of recently published information on the biological and mechanistic aspects of cataracts induced by exposure to ionizing radiation (IR). The data were compiled by assessing the pertinent literature in several distinct areas which contribute to the understanding of IR induced cataracts, information regarding lens biology and general processes of cataractogenesis. Results from cellular and tissue level studies and animal models, and relevant human studies, were examined. The main focus was the biological effects of low linear energy transfer IR, but dosimetry issues and a number of other confounding factors were also considered. The results of this review clearly highlight a number of gaps in current knowledge. Overall, while there have been a number of recent advances in understanding, it remains unknown exactly how IR exposure contributes to opacification. A fuller understanding of how exposure to relatively low doses of IR promotes induction and/or progression of IR-induced cataracts will have important implications for prevention and treatment of this disease, as well as for the field of radiation protection.

Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research.

Lens opacities or cataract(s) represent a universally important cause of visual impairment and blindness. Typically, cataract is acquired with aging as a complex disorder involving environmental and genetic risk factors. Cataract may also be inherited with an early onset either in association with other ocular and/or systemic abnormalities or as an isolated lens phenotype. Here we briefly review recent advances in gene discovery for inherited and age-related forms of cataract that are providing new insights into lens development and aging.

Molecular Genetics of Cataract

Purpose To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population. Methods Based on the hypothesis that most arCC patients in consanguineous families in the Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes. Results Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4. Conclusions The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population.

Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening

Role of carcinogenesis related mechanisms in cataractogenesis and its implications for ionizing radiation cataractogenesis.

Alpha A-crystallin (CRYAA) is considered critical for the maintenance of lens transparency and is related to the pathogenesis of age-related cataracts (ARCs), especially the nuclear subtype. As the 5′ untranslated region (5′ UTR) modulates gene expression, the purpose of current study was to investigate whether single nucleotide polymorphisms (SNPs) in the 5′ UTR of CRYAA were associated with susceptibility to ARC in a Han Chinese population and to clarify the mechanism of this association. SNPs in the 5′ UTR (−1 to −1000) of CRYAA were identified in 243 nuclear ARC patients and 263 controls using polymerase chain reaction and DNA sequencing. Allele and genotype frequencies were calculated and compared between two groups. Haploview 4.2 was used to calculate the linkage disequilibrium index, and the SHEsis analysis platform was used to infer haplotype construction. A dual-luciferase reporter gene assay was used for transcription of CRYAA in the presence of a protective haplotype with individual SNP alteration, Chromatin immunoprecipitation (ChIP) was employed to determine whether SNPs regulated CRYAA expression by altering the binding affinity of transcription factors. Three polymorphisms were identified in the 5′ UTR of CRYAA: rs3761381 (P = 0.000357, odds ratio [OR] = 1.837), rs13053109 (P = 0.788, OR = 1.086), and rs7278468 (P = 0.00136, OR = 0.652). The haplotype C-G-T (P = 0.0014, OR = 1.536) increased the risk of nuclear ARC, whereas the haplotype T-G-G (P = 0.00029, OR = 0.535) decreased the risk. The haplotype C-G-T decreased CRYAA transcription through rs7278468, which is located in the binding site of specificity protein 1 (Sp1). Furthermore, the G allele of rs7278468 increased CRYAA transcription by enhancing the binding affinity of Sp1. These data indicate that the CRYAA polymorphism is a genetic marker of inter-individual differences in the risk of nuclear ARC.

/pdf/association-of-alpha-a-crystallin-polymorphisms-with-19v7ktnzsv.pdf

Association of alpha A-crystallin polymorphisms with susceptibility to nuclear age-related cataract in a Han Chinese population

Background 
Recent clinical studies have assessed the association of various polymorphisms on the ephreceptor tyrosinekinase-type A2 (EPHA2) with the risk for age-related cataract in populations of different ethnic/racial backgrounds, but inconsistent results have been obtained.
Objective 
This meta-analysis aimed to identify if any polymorphism(s) might be commonly present in different ethnic/racial populations in association with the age-related cataract risk.
Methods 
The PubMed and Web of Science databases (up to December 1, 2012) were searched for clinical studies on the association of EPHA2 polymorphisms with the risk for age-related cataract. The polymorphisms that were assessed in all eligible studies were analyzed for their association with the risk for age-related cataract using different models.
Results 
Three studies were identified, which were conducted, respectively, on white Americans in the Unites States and on Asians in Indian and China. The polymorphism, rs3754334, was the only one studied in all these three studies and was therefore the focus of this meta-analysis. No publication bias or heterogeneity was found. Our analysis results demonstrated that rs3754334 was associated with the risk of any cataracts in the recessive (OR = 1.202, 95% CI: 1.051–1.375, P = 0.007) and Codominant (OR = 1.194, 95% CI: 1.035–1.378, P = 0.015) models, but its association with cortical or nuclear phenotype of age-related cataract was not evident.
Conclusion 
Polymorphism, rs3754334, might be a variant on the EPHA2 gene that is commonly associated with the risk for age-related cataract in different ethnical and geographical populations.

/pdf/association-of-the-ephreceptor-tyrosinekinase-type-a2-epha2-ysoi1td0pa.pdf

Association of the Ephreceptor Tyrosinekinase-Type A2 (EPHA2) Gene Polymorphism rs3754334 with Age-Related Cataract Risk: A Meta-Analysis

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Association of the Ephreceptor Tyrosinekinase-Type A2 (EPHA2) Gene Polymorphism rs3754334 with Age-Related Cataract Risk: A Meta-Analysis