Dataset Information

Association of FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile Polymorphisms with Congenital Cataract and Microphthalmia.

ABSTRACT: Purpose:To investigate the association of FOXE3-p.Ala170Ala (rs34082359) and PITX3-p.Ile95Ile (rs2281983) polymorphisms with congenital cataract and microphthalmia in a western Indian population. Methods:FOXE3-p.Ala170Ala (c.510C>T) and PITX3-p.Ile95Ile (c.285C>T) polymorphisms were genotyped in 561 subjects consisting of 242 cases with congenital cataract, 52 with microphthalmia, and 267 controls using polymerase chain reaction-restriction fragment length polymorphism. Approximately 10% of samples were randomly sequenced for each single nucleotide polymorphism to confirm the genotypes. The prediction of mRNA secondary structure for polymorphism FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile was performed. Results:A significantly high frequency of T allele and a borderline significance in the frequency of TT genotype of FOXE3-p.Ala170Ala was observed in microphthalmia cases, as compared to controls [T allele: OR: [CI] = 1.8 [1.15-2.72], P = 0.0115; TT: OR [CI] = 2.9 [1.14-7.16], P = 0.0291). The frequency of CC genotype was significantly low in microphthalmia cases when compared to controls (CC: OR [CI] = 0.5 [0.24-0.86, P = 0.0150). There was no significant difference in the allele and genotype frequencies of PITX3-p.Ile95Ile between cases and controls. A slight free energy change was observed in the secondary structure of mRNA between the FOXE3-p.Ala170Ala C-allele (-917.60 kcal/mol) and T-allele (-916.80 kcal/mol) and between PITX3-p.Ile95Ile C-allele (-659.80 kcal/mol) and T-allele (-658.40 kcal/mol). Conclusion:The present findings indicate that FOXE3-p.Ala170Ala 'T' allele and 'TT' genotype could be predisposing factors for microphthalmia while 'CC' genotype might play a protective role against it. A reduction in the free energy change associated with FOXE3-p.Ala170Ala 'T' allele could further contribute towards disease risk.

SUBMITTER: Vidya NG

PROVIDER: S-EPMC6210873 | biostudies-literature | 2018 Oct-Dec

REPOSITORIES: biostudies-literature

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Association of <i>FOXE3</i>-p.Ala170Ala and <i>PITX3</i>-p.Ile95Ile Polymorphisms with Congenital Cataract and Microphthalmia.

Vidya Nair Gopinathan NG Ganatra Darshini D Vasavada Abhay R AR Rajkumar Sankaranarayanan S

Journal of ophthalmic & vision research 20181001 4

<h4>Purpose</h4>To investigate the association of <i>FOXE3</i>-p.Ala170Ala (rs34082359) and <i>PITX3</i>-p.Ile95Ile (rs2281983) polymorphisms with congenital cataract and microphthalmia in a western Indian population.<h4>Methods</h4><i>FOXE3</i>-p.Ala170Ala (c.510C>T) and <i>PITX3</i>-p.Ile95Ile (c.285C>T) polymorphisms were genotyped in 561 subjects consisting of 242 cases with congenital cataract, 52 with microphthalmia, and 267 controls using polymerase chain reaction-restriction fragment len ...[more]

PMID: 30479708

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Project description:Aniridia and congenital cataract represent rare but severe developmental ocular conditions. We examined 33 probands from France for mutations in several transcription factors associated with these phenotypes, the forkhead box E3 (FOXE3), paired box gene 6 (PAX6), paired-like homeodomain transcription factor 2 (PITX2), and paired-like homeodomain transcription factor 3 (PITX3) genes.Out of 33 probands, 27 were affected with congenital cataract while the remaining six were affected with aniridia (with or without cataract). The coding regions of FOXE3, PAX6, PITX2, and PITX3 were examined by direct DNA sequencing of gene-specific PCR products.A novel dominant mutation at the stop codon of FOXE3, c.959G>C (p.X320SerextX72), was identified in a patient with congenital cataract. Another novel FOXE3 sequence change, c.571-579dup (p.Tyr191_Pro193dup), was identified in a patient with aniridia, mild lens opacities, and some additional ocular defects; this patient was also found to carry a nonsense mutation in PAX6. PAX6 mutations were identified in two additional probands with aniridia and cataracts. None of the observed sequence alterations were found in normal controls. No mutations were identified in PITX2 or PITX3.The p.X320SerextX72 mutation is only the fourth FOXE3 allele associated with a dominant phenotype since the majority of FOXE3 mutations appear to be recessive with no phenotype observed in heterozygous carriers. The encoded protein is predicted to contain a complete normal sequence followed by seventy-two erroneous amino acids; the position and effect of this mutation are similar to two of the previously reported dominant changes, suggesting a common mechanism for dominant alleles. The p.Tyr191_Pro193dup is predicted to result in an in-frame duplication of three amino acids; however, the contribution of this mutation to the phenotype is unclear since the affected patient also carries a nonsense mutation in PAX6 which acts upstream of FOXE3 in the molecular pathway. The identified PAX6 mutations correspond to the two most commonly observed mutant alleles and demonstrate phenotypes that are consistent with the previously reported spectrum.

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Dataset Information

Association of FOXE3-p.Ala170Ala and PITX3-p.Ile95Ile Polymorphisms with Congenital Cataract and Microphthalmia.

Publications

Association of <i>FOXE3</i>-p.Ala170Ala and <i>PITX3</i>-p.Ile95Ile Polymorphisms with Congenital Cataract and Microphthalmia.

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