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J. A. Aragon-Martin, A. Child, G. Brice, M. Sarfarazi; Candidate Gene Screening of Primary Open Angle Glaucoma (POAG) at the GLC1C Locus. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4036.
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© ARVO (1962-2015); The Authors (2016-present)
The published GLC1C locus maps within a 7.88-Mb region that is flanked by 2 DNA markers of D3S3637 and D3S3694. We aimed to reduce this region by family-based linkage analysis and to further screen a series of candidate genes in a group of adult-onset POAG families that exhibited potential genetic linkage to this region.
POAG families were selected for detailed DNA genotyping, haplotype construction and segregation analysis. Sequence specific primers flanking the intron-exon boundaries of candidate genes were used to screen their respective PCR-amplified products by direct DNA sequencing.
One large family with 6 living POAG members showed a crucial recombination with D3S3612 in an affected subject, thus suggesting that the GLC1C region may be limited to only 1.32-Mb on 3q23. This new region contains at least 10 known (ACPL2, ZBTB38, RASA2, RNF7, GRK7, ATP1B3, TFDP2, GK5, XRN1 and ATR) and 2 other predicted genes (LOC646730 and LOC729687). Our recent genome scan data also identified 7 adult-onset POAG families that are potentially linked to this refined region. Screening of affected subjects of these families with all the 10 known genes (total of 159 exons encoding for 8,741 residues) identified a total of 90 DNA alterations, including 73 intronic and 17 exonic variations, of which 28 and 7 respectively, were new SNPs. The 7 non-synonymous alterations observed in ZBTB38 (P300A, S319A, N617D), GRK7 (E443G, P460T) and ATR (M211T, R2606Q) were all considered as non-disease causing variations. Although no mutations were found within the coding regions of these 10 genes, other mutations within their non-coding or regulatory regions cannot be ruled out.
Although the GLC1C locus may be limited to a region of only 1.32-Mb, none of the current 10 known genes from this region is involved in the etiology of POAG families that we screened. Therefore, it is important to screen the other 2 predicted genes from this region, which may contribute to the pathogenesis of the GLC1C glaucoma.
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