The EPHA2 Gene is Associated with Cataracts Linked to Chromosome 1p

Overview

Journal Mol Vis

Specialties Cell Biology
Molecular Biology
Ophthalmology

Date 2008 Nov 14

PMID 19005574

Citations 101

Authors

Alan Shiels

Thomas M Bennett

Harry L S Knopf

Giovanni Maraini

Anren Li

Xiaodong Jiao

J Fielding Hejtmancik

Affiliations

Soon will be listed here.

Abstract

Purpose: Cataracts are a clinically and genetically heterogeneous disorder affecting the ocular lens, and the leading cause of treatable vision loss and blindness worldwide. Here we identify a novel gene linked with a rare autosomal dominant form of childhood cataracts segregating in a four generation pedigree, and further show that this gene is likely associated with much more common forms of age-related cataracts in a case-control cohort.

Methods: Genomic DNA was prepared from blood leukocytes, and genotyping was performed by means of single nucleotide polymorphism (SNP) markers, and short tandem repeat (STR) markers. Linkage analyses were performed with the GeneHunter and MLINK programs, and association analyses were performed with the Haploview and Exemplar programs. Mutation detection was achieved by PCR amplification of exons and di-deoxy cycle-sequencing.

Results: Genome-wide linkage analysis with SNP markers, identified a likely disease-haplotype interval on chromosome 1p (rs707455-[approximately 10 Mb]-rs477558). Linkage to chromosome 1p was confirmed using STR markers D1S2672 (LOD score [Z]=3.56, recombination distance [theta]=0), and D1S2697 (Z=2.92, theta=0). Mutation profiling of positional-candidate genes detected a heterozygous transversion (c.2842G>T) in exon 17 of the gene coding for Eph-receptor type-A2 (EPHA2) that cosegregated with the disease. This missense change was predicted to result in the non-conservative substitution of a tryptophan residue for a phylogenetically conserved glycine residue at codon 948 (p.G948W), within a conserved cytoplasmic domain of the receptor. Candidate gene association analysis further identified SNPs in the EPHA2 region of chromosome 1p that were suggestively associated with age-related cataracts (p=0.007 for cortical cataracts, and p=0.01 for cortical and/or nuclear cataracts).

Conclusions: These data provide the first evidence that EPHA2, which functions in the Eph-ephrin bidirectional signaling pathway of mammalian cells, plays a vital role in maintaining lens transparency.

Citing Articles

Oxidative Stress in Genetic Cataract Formation.

Hejtmancik J Antioxidants (Basel). 2024; 13(11).

PMID: 39594457 PMC: 11591473. DOI: 10.3390/antiox13111315.

Spatial-temporal comparison of Eph/Ephrin gene expression in ocular lenses from aging and knockout mice.

Huynh P, Cheng C Front Ophthalmol (Lausanne). 2024; 4:1410860.

PMID: 38984128 PMC: 11182306. DOI: 10.3389/fopht.2024.1410860.

Through the Gateway: A Brief History of Cataract Genetics.

Shiels A Genes (Basel). 2024; 15(6).

PMID: 38927721 PMC: 11202810. DOI: 10.3390/genes15060785.

Abnormal function of /p.R957P mutant in congenital cataract.

Zhang J, Cao Z, Zhou B, Yang J, Li Z, Lin S Int J Ophthalmol. 2024; 17(6):1007-1017.

PMID: 38895685 PMC: 11144770. DOI: 10.18240/ijo.2024.06.04.

EPHA2 Receptor as a Possible Therapeutic Target in Viral Infections.

Vincenzi M, Mercurio F, Leone M Curr Med Chem. 2023; 31(35):5670-5701.

PMID: 37828671 DOI: 10.2174/0109298673256638231003111234.

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