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  IN THIS Article
 ::  Abstract
 :: Introduction
 ::  Materials and Me...
 :: Results
 :: Discussion
 :: Acknowledgments
 ::  References
 ::  Article Figures
 ::  Article Tables

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  Table of Contents     
ORIGINAL ARTICLE
Year : 2011  |  Volume : 57  |  Issue : 3  |  Page : 201-205

Polymorphisms of the gamma crystallin A and B genes among Indian patients with pediatric cataract


1 Department of Biological Sciences, Birla Institute of Technology and Science- Pilani, Hyderabad Campus, Hyderabad, Andhra Pradesh, India
2 Iladevi Cataract and IOL Research Centre, Memnagar, Ahmedabad, Gujarat, India

Date of Submission21-Nov-2010
Date of Decision02-Feb-2011
Date of Acceptance10-Mar-2011
Date of Web Publication22-Sep-2011

Correspondence Address:
S Kapur
Department of Biological Sciences, Birla Institute of Technology and Science- Pilani, Hyderabad Campus, Hyderabad, Andhra Pradesh
India
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Source of Support: Grants from Indian Council of Medical Research, New Delhi, India to Dr. Suman Kapur and ICMR senior research fellowship to Mrs. Shipra Mehra, Conflict of Interest: There is no conflict of interest among any of the authors of the paper being submitted


DOI: 10.4103/0022-3859.85205

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 :: Abstract 

Background : Previous familial studies have reported co-segregation of mutation in gamma crystallin A and B CRYGA and CRYGB genes with childhood cataract. Aim : We investigated association of nucleotide variations in these genes in subjects with and without pediatric cataract from India. Settings and Design : The study included 195 pediatric subjects including healthy children with no ocular defects and pediatric cataract cases. Materials and Methods : Subjects were genotyped by PCR-RFLP method for exonic and intronic genetic variations in CRYGA and CRYGB. Statistical Analysis : The association of these polymorphisms with cataract was estimated by two way contingency tables and the risk allele was also analyzed for their functional impact using in silico tools. Results : No significant difference was observed between cases and control subjects for the frequencies of SNPs G198A (Intron A), T196C (Exon 3) of CRYGA and G449T (Exon 2) of CRYGB gene. -47C allele of rs2289917 in CRYGB showed the strongest association with cataract (Odd Ratio-OR=3.34, 95% Confidence Interval-CI 95% =1.82-6.12, P=0.00007). In silico analyses revealed that this polymorphism lies in a phylogenetically conserved region and impacts binding of a transcription factor, viz. progesterone receptor (PR) to CRYGB promoter. Conclusion : rs2289917 risk allele showed a strong association with increased vulnerability for pediatric cataract. The findings suggest that this association may be a secondary phenomenon related to genetic variation playing critical role in lens development during perinatal and/or pediatric growth. Present exploratory study provides a basis for further defining the role of PR as a regulator of CRYG locus in lens formation/transparency.


Keywords: Cataract, CRYGA gene, CRYGB gene, gender, PCR-RFLP, progesterone receptor


How to cite this article:
Mehra S, Kapur S, Vasavada A R. Polymorphisms of the gamma crystallin A and B genes among Indian patients with pediatric cataract. J Postgrad Med 2011;57:201-5

How to cite this URL:
Mehra S, Kapur S, Vasavada A R. Polymorphisms of the gamma crystallin A and B genes among Indian patients with pediatric cataract. J Postgrad Med [serial online] 2011 [cited 2019 Nov 19];57:201-5. Available from: http://www.jpgmonline.com/text.asp?2011/57/3/201/85205



 :: Introduction Top


Cataract in children is particularly serious because it has the potential for inhibiting visual development, resulting in permanent blindness and disability. About one-third to one-half of all bilateral pediatric cataracts have a genetic basis. [1] Out of the 39 mapped loci for isolated pediatric cataracts, more than 26 loci have been associated with mutations in specific genes and half of these are reported in crystallin (CRY) genes. [2] Studies have located autosomal dominant congenital cataract (ADCC) causing mutations to g-crystallin (CRYG) gene cluster (CRYGA-F) located at 2q33-35. [3] Infact the chromosomal region from 198 Mb to 220 Mb on chromosome 2q has been repeatedly found to host the disease haplotype for pediatric cataract. Even the largest subgroup of mutations causing mouse cataracts affects the CRYG locus only. [4] However, unlike mouse models, cataract-causing mutations in humans have been simply detected in the CRYGC and CRYGD genes, which are also the most expressed genes in humans. [1],[5],[6],[7],[8],[9]

The fact that several studies with evidence of suggestive linkage signals at this loci and comprehensive screening of known cataract causing mutations in associated genes have failed to map the contributing lesion in significant proportion of pedigrees analyzed [5],[10],[11] suggests the presence of other genes or sequence elements involved in pathogenesis of cataract. [1] Similarly, even though mutations and polymorphisms in CRYGA and CRYGB genes have been frequently reported in familial linkage studies on congenital cataract but their role in cataract pathogenesis still remains ambiguous. [12],[13],[14],[15] Santhiya et al., 2002 reported variation G198A of Intron A in CRYGA gene at a fairly high frequency in cases of ADCC. Similarly -47→T→C (rs2289917) polymorphism occurred in 50% of cases in a heterozygous condition in south Indian population. [12] Kapur et al., 2009 detailed the population frequency of some of the reported exonic SNP's of CRYGA (T196C - Exon 3) and CRYGB (G449T - Exon 2) and found virtually monomorphic existence of these in western Indian population. [16] The non-coding single nucleotide polymorphism (SNP) in CRYGA (G198A -Intron A) was highly prevalent (0.72), while the allele frequency of promoter SNP of CRYGB (rs2289917) varied significantly (P=0.02) among pediatric and adult healthy subjects. A significant difference between allele frequencies of rs2289917 in western Indian healthy volunteers verses the frequency reported in ADCC cases of south Indian population was observed. [16] Taking clues from the earlier reports, the present study was thus extended to cataract patients to determine the association of CRYGA and CRYGB SNPs with childhood cataract among Asian Indian population in a case-control study design.


 :: Materials and Methods Top


Subject recruitment

This pilot study on childhood cataract was a joint initiative undertaken by local eye hospital and academic institution, namely BITS, Pilani. Children below 12 years of age, who were admitted in hospital for cataract surgery, subsequent to a confirmed diagnosis of childhood cataract, were recruited for this study during the period from May 2005 to December 2006. The study was approved by the Ethics committee of the participating institutions and was conducted within the norms of Declaration of Helsinki for human experimentation. An informed consent from the parents/guardians of all children and a duly signed child assent form for children ≥7-12 years of age was obtained if he or she was capable of doing so. The probands underwent clinical eye examination by a senior ophthalmologist to assess the cataract phenotype through either slit lamp or direct ophthalmoscope depending on the cooperation level of the subject. The type of cataract was recorded according to the morphological classification proposed by Merin, 1974. [17] Patients with uveitis, cataract due to trauma, steroid therapy or infective etiology, cataract with associated glaucoma or retinal pathology or subluxated lens and patients' positive for TORCH were excluded from the present study. Controls were drawn from the same ethnic population and geographical region as the patients. Only those healthy volunteers were recruited for the study which qualified as a control if (a) they were <12 years of age, (b) had no history of congenital/infantile, juvenile, traumatic/post-surgical cataract or any other detectable ocular defects.

Molecular analysis

Genomic DNA was obtained from 79 volunteers having no history of cataract and 116 patients of childhood cataract using method described elsewhere. [18] Genomic DNA was subjected to polymerase chain reaction (PCR) employing primers reported by Santhiya et al., 2002 and mutation screening was performed by restriction fragment length polymorphism (RFLP) as reported earlier. [12],[16] A total of 10% samples were repeated for confirmation of allele type and the sequence variation was further confirmed by commercial DNA sequencing of representative samples. Chi-square (χ2 ) test and Odds ratios (OR) with 95% Confidence Interval (CI 95% ) was used to test differences between the cases and controls using Med Calc version 9.3.9.0. Bonferroni correction was applied to the P values (P≤0.05). Hardy-Weinberg equilibrium (HWE) was tested by the Michael Court online calculator. [19] Estimation of conservation of the gene sequence across the various species was conducted by aligning (multiple sequence alignment - MSA) multiple nucleotide sequences of primates and rodents obtained from NCBI with the reference human CRYGB gene sequence using CLUSTAL W and NCBI-BLAST. [20],[21] Meaningful MSA of some divergent nucleotide sequences obtained after direct sequencing of CRYGB gene was also performed. The identities, similarities and differences were noted and analyzed for their putative role by in silico methods. The sequence changes in the promoter region were investigated for changes in transcription factor (TF) binding site by TRANSFEC (version 4) algorithm of ALIBABA16 software. [16]


 :: Results Top


Of the 79 control subjects, mean age 5.43±3.6 years, 69% were males and remaining 31% were females. Similarly among 116 patients with cataract, mean age 5.23±3.9 years, 64% were males and 36% were females. A total of 90% cases were simplex/sporadic cataract cases with majority of them having bilateral cataract (80%). Only 10% of the recruited cases reported a positive family history for cataract. Zonular cataract was observed in 47% of eyes examined, followed by total (31%) and polar (14%) opacities. Membranous cataract was seen in mere 5% of the recruited patient cohort and the rest 4% of cases had cataract associated with pre-existent posterior capsule defect and with pulfrich phenomenon. [Table 1] details the genotype and allele frequency of SNPs in CRYGA and CRYGB genes showing differences in frequencies among cataract cases and controls. The observed genotype frequency of rs796280 and rs2289917 variation satisfies HWE (P>0.05) in the control group eliminating any selection bias. The frequency of "A" allele of rs796280 of CRYGA gene did not differ significantly between the cases and controls (OR=0.81, CI 95%= 0.68-1.12, P=0.29, [Table 1] nor frequency of "AA" genotype reach a statistical significant difference between the two groups (OR=1.11, CI 95%= 0.44-2.75, P=0.81). In contrast, the "C" allele distribution of rs2289917 differed markedly between pediatric cataract cases and control subjects (OR for allele "C"=3.34, CI 95%= 1.82-6.13, P=0.00007, two tailed; [Table 1]. Presence of the "CC" genotype emerged as an even stronger association with an OR=4.19, CI 95%= 2.10-8.38, P=0.00004. Based on the sample size and the minor allele frequency in the control group the present pilot study had a power of 75%. The "C" allele distribution of rs2289917 did not differ between the unilateral and bilateral cataract cases and did not show any association with any observed endophenotypes of cataract. The other two SNP's studied, namely, T196C of CRYGA (Exon 3) and G449T of CRYGB (Exon 2) genes were found to be monomorphic in our cohort (both cases and controls). No database records were available for comparison of frequencies for CRYGA T196C (Exon 3) and CRYGB G449T (Exon 2).
Table 1: Genotype and allele distribution of SNPs in CRYGA and CRYGB genes


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MSA of promoter region of CRYGB gene in various species, including primates and rodents revealed that -47 nucleotide position upstream of CRYGB transcription start point (90 th nucleotide of NCBI accession no. M11970.1) is located in a highly conserved region of the CRYGB gene [Figure 1]. [22] Further analysis by ALIBABA software showed that the sequence containing "C" allele, i.e., -47C of rs2289917 has binding sites for two TFs, namely - ACE2 (member of CLB2 cluster) and progesterone receptor (PR), while substitution by "T" at this position results in the loss of both these TF binding sites. [16] The results of putative changes in TF binding sites due to other novel variation observed after MSA are also summarized in [Table 2]. Variation at the 49 th and the 51 st nucleotide position of CRYGB nucleotide sequence (Accession No. M11970.1) leads to loss of TF-binding sites for NF-kappa B, c-Ets-1_68, C/EBPalpha, Sp1 and NF-1 in the promoter region.
Table 2: Promoter analysis: Changes in transcription factor-binding sites in the 5' upstream region of CRYGB gene in pediatric cataract cases


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Figure 1: MSA for the promoter region of CRYGB across various species

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 :: Discussion Top


The present study explored the prevalence of genotypes and alleles of SNPs in CRYGA and CRYGB genes and their association with childhood cataract. A 3-fold increased risk observed in the presence −47C allele of rs2289917 among cases, implicates a molecular lesion that may predispose an infant to congenital cataract. The fact that nearest SNP (G449T Exon 2 CRYGB gene) studied to rs2289917 is monomorphic and this SNP is contained in a high linkage disequilibrium (LD) block in HapMap database (D'=1, Log of Odds score-LOD >2) further makes this finding very robust and indicates a strong association. [23] Indeed, Santhiya et al., have earlier shown a co-segregation of rs2289917 SNP with ADCC and Rogaev et al., have also reported an association of a repeat marker, located within CRYGB gene, with polymorphic congenital cataract. [12],[13],[24] Three independent reports of a missense, a point mutation and a nucleotide substitution in the CRYGB gene of animal models of cataract co-segregate with the cataract phenotype as well. [25],[26],[27] The association of rs2289917 with pediatric cataract also substantiates the earlier findings which have shown that CRYG expression is maximal at birth in mice and is differentially inactivated during postnatal development. [28],[29] Indeed, CRYGB gene is the last actively expressed gene in the rat lens, and it's expression is attenuated after three months of birth. [30] Additionally, Goring et al. have proposed that upstream enhancers and proximal promoter elements of CRYG genes alone have the capacity to direct gene expression in the lens fiber cells during early stages of lens growth and development. [31] Thus, sequence variation in this region of the gene may play a pivotal role in initial period of lens development through pre- and peri-natal periods. In this respect, the present study is the first to explore the putative role of the upstream region of CRYGB gene in lens development and/or transparency.

MSA data further confirmed CRYGB promoter region to be phylogenetically conserved. Sequence analysis of different CRYG genes had previously revealed that nucleotide sequence between −67bp to −25bp is highly conserved and functions as a strong transcriptional activator. This region act as an important hub at which nuclear factors from lens and non-lens cells can bind and form complexes which correlate well with lens-specific promoter activity of crystallins. [32] However, no studies have directly explored the role of nucleotide variation/s occurring in the upstream region of CRYGB promoter with development of childhood cataract in humans. In silico analyses of nucleotide sequence variations revealed putative changes in TF-binding sites due to novel mutation observed between −88 to −47 nucleotide positions (49-90 th nucleotide position of M11970.1) in the upstream region of CRYGB gene. These variations caused loss of TF binding sites for factors such as NF-kappaB, Sp1 and NF-1 in addition to PR and ACE2. All these transcription factors are imperative for cell proliferation, gene expression and survival in the early developmental stages in eye tissues. [33],[34],[35],[36],[37]

The study also surveyed the relationship between loss/gain of PR TF-binding site and cataract. Cases bearing −47CC genotype of rs2289917 possessed a PR-binding site in the promoter of CRYGB gene had >4-fold increased risk for developing childhood cataract. PR belongs to a class of steroid hormone receptor super-family, which includes glucocorticoid receptor (GR) with both having similar sequence and structural characteristics. Numerous studies have documented the cross-talk between PR and GR due to overlapping ligand binding and have reported GR like effects mediated by progesterone in various tissues. [38] It is also well established that glucocorticoids alter expression of several genes in lens epithelial cells, including those responsible for lens transparency, and hence play a direct role in normal lens development and/or cataractogenesis. [39],[40],[41] Therefore, it is proposed that there exists a probable window during which lens development seems to be sensitive to PR such that "T" allele (lacking the PR-binding site) carrying individuals would apparently be protected from childhood cataract in contrast to those possessing the "C" allele. However, in order to completely unravel the role of this gene in the etiology of cataract the present exploratory study, with limited power, needs to be replicated in a larger cohort and in different populations across the world.


 :: Acknowledgments Top


The authors gratefully acknowledge the financial support received from the Indian Council of Medical Research (ICMR), Government of India, New Delhi in the form of an extramural grant to Dr. Suman Kapur and senior research fellowship to Ms. Shipra Mehra. Further the technical help of Dr. Devarshi Gajjar and Dr. Manav Kapoor is gratefully acknowledged.

 
 :: References Top

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    Figures

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    Tables

  [Table 1], [Table 2]

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