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Molecular and structural analysis of genetic variations in congenital cataract.

ABSTRACT: OBJECTIVE: To determine the relative contributions of mutations in congenital cataract cases in an Indian population by systematic screening of genes associated with cataract. METHODS: We enrolled 100 congenital cataract cases presenting at the Dr. R. P. Centre for Ophthalmic Sciences, a tertiary research and referral hospital (AIIMS, New Delhi, India). Crystallin, alpha A (CRYAA), CRYAB, CRYGs, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, beaded filament structural protein 1 (BFSP1), gap function protein, alpha 3 (GJA3), GJA8, and heat shock transcription factor 4 gene genes were amplified. Protein structure differences analysis was performed using Discovery Studio (DS) 2.0. RESULTS: The mean age of the patients was 17.45±16.51 months, and the age of onset was 1.618±0.7181 months. Sequencing analysis of 14 genes identified 18 nucleotide variations. Fourteen variations were found in the crystallin genes, one in Cx-46 (GJA3), and three in BFSP1. CONCLUSIONS: Congenital cataract shows marked clinical and genetic heterogeneity. Five nucleotide variations (CRYBA4:p.Y67N, CRYBB1:p.D85N, CRYBB1:p.E75K, CRYBB1:p.E155K, and GJA3:p.M1V) were predicted to be pathogenic. Variants in other genes might also be involved in maintaining lens development, growth, and transparency. The study confirms that the crystallin beta cluster on chromosome 22, Cx-46, and BFSP1 plays a major role in maintaining lens transparency. This study also expands the mutation spectrum of the genes associated with congenital cataract.

SUBMITTER: Kumar M

PROVIDER: S-EPMC3850972 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Molecular and structural analysis of genetic variations in congenital cataract.

Kumar Manoj M Agarwal Tushar T Kaur Punit P Kumar Manoj M Khokhar Sudarshan S Dada Rima R

Molecular vision 20131124

<h4>Objective</h4>To determine the relative contributions of mutations in congenital cataract cases in an Indian population by systematic screening of genes associated with cataract.<h4>Methods</h4>We enrolled 100 congenital cataract cases presenting at the Dr. R. P. Centre for Ophthalmic Sciences, a tertiary research and referral hospital (AIIMS, New Delhi, India). Crystallin, alpha A (CRYAA), CRYAB, CRYGs, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, beaded filament structural protein 1 (BFSP1), ga ...[more]

PMID: 24319337

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Project description:BackgroundCongenital cataract (CC) and congenital heart disease (CHD) are significant birth defects. In clinical practice, the concurrence of CC and CHD is frequently observed in patients. Additionally, some monogenic diseases, copy number variation (CNV) syndromes, and diseases associated with intrauterine infection involve both cataract and heart defects. However, little is known about the association between CC and CHD. Here, we characterised the demographic, clinical, and genetic features of patients with CC and heart defects.MethodsMedical records for 334 hospitalised patients diagnosed with CC were reviewed. Demographic and clinical features of patients with CC with and without CHD were compared. Clinical and genomic information for patients with 'cataract' and 'cardiac defects' were reviewed from Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). Microarray-based comparative genomic hybridisation and whole-exome sequencing were performed in 10 trio families with CC and CHD to detect de novo genomic alterations, including copy number variants and single nucleotide changes.ResultsIn a retrospective analysis of 334 patients with CC over the past 10 years at our hospital, we observed a high proportion of patients (41.13%) with CHD (including innocent CHD, which reported as left-to-right shunt in echocardiography test). The CC with CHD group had higher incidences of preterm birth and Down's syndrome than the CC without CHD group. Atrial septal defect was the most frequent heart defect. A total of 44 cases with cataracts and heart diseases were retrieved from Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER). In total, 52 genomic alterations were reported, 44% of which were de novo germline variants. In the 10 trio families with CC and CHD, we found de novo CNVs responsible for two well-known chromosomal disorders and identified a novel pathogenic mutation in GJA8 responsible for CC.ConclusionsWe observed significant associations between CHD and CC in our 10-year patient cohort. Based on the cohort and data from DECIPHER, developmental syndromes in some patients were due to genetic defects, thus explaining the concurrence of CC and CHD. Additionally, we detected de novo mutations as an independent cause of cataracts. Our findings suggest that developmental syndromes in patients with CC deserve more attention in clinical practice by ophthalmologists.

Project description:PURPOSE: Age-related cataract (ARC) is a complex multifactorial disorder, including genetic and environmental factors. Ezrin (EZR), a member of the ezrin/radixin/moesin (ERM) protein family, plays a crucial role in the development of the lens as a plasma membrane-cytoskeleton linker. We conducted this study to investigate the role of genetic variations of ezrin and the relationship between single nucleotide polymorphisms (SNPs) in EZR and susceptibility to ARC in a Chinese population. METHODS: A total of 205 sporadic age-related cataract patients and 218 unrelated random healthy controls participated in our study. Genomic DNA was extracted from peripheral blood leukocytes. All exons of EZR were sequenced after being amplified with polymerase chain reaction. The functional consequences of the mutations were analyzed using PolyPhen2. SNP statistical analysis was performed using SNPstats. RESULTS: We found three novel variations in 205 patients. None presented in the 218 controls, including c.441C>G, c.924G>C, and c.1503G>A. PolyPhen2 predicted that the c.924G>C mutation probably had pathogenicity. Compared with the healthy controls, the rs5881286 -/GT genotype and - allele frequencies (p=0.0012; odds ratio [OR]=3.37; 95% confidence interval [CI]=1.70-6.70; p=3.96e-5; ?(2)=18.98, respectively), rs2242318 T/C genotype and C allele frequencies (p=0.0045; OR=3.40; 95% CI=1.70-6.79; p=8.82e-6; ?(2)=21.86, respectively), and rs144581330 A/G genotype and G allele frequencies (p=0.0472; OR=14.46; 95% CI=1.29-162.43; p=0.0244, ?(2)=6.99, respectively) were higher in the patients with age-related cataract. SNP rs144581330 in exon 2 was also predicted to be probably damaging by PolyPhen2. Haplotype association including the - allele of rs5881286, C allele of rs2242318, and A allele of rs144581330 exhibited significantly higher distribution in the patients with ARC (p=8.0e-4; OR=3.38; 95% CI=1.66-6.87). CONCLUSIONS: This study suggests that the genetic variations and SNPs in the gene EZR possibly contribute to the development of age-related cataracts in the Chinese population.

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Molecular and structural analysis of genetic variations in congenital cataract.

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Molecular and structural analysis of genetic variations in congenital cataract.

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