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X. Jiao, A. Shiels, T. M. Bennett, H. L. S. Knopf, G. Maraini, J. F. Hejtmancik; The EPHA2 Gene Is Associated With Inherited Cataracts Linked to Chromosome 1p. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2823.
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© ARVO (1962-2015); The Authors (2016-present)
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 4-generation pedigree, and further show that polymorphisms in this gene may be associated with a much more common form of age-related cataracts in a case-control cohort.
Genomic DNA was prepared from blood leucocytes, 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.
Genome-wide linkage analysis with SNP markers, identified a likely disease-haplotype interval on chromosome 1p (rs707455-[~10Mb]-rs477558). Linkage to chromosome 1p was confirmed using STR markers D1S2672 (LOD score [Z] = 3.56, recombination distance [θ] = 0), and D1S2696 (Z = 2.92, θ = 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 co-segregates with cataracts. 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 1p that were suggestively associated with age-related (cortical, cortical and/or nuclear) cataracts (p = 0.007, 0.01).
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. Additional studies are underway confirming the association of EPHA2 SNPs with cortical and nuclear cataracts in additional ethnic groups.
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