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Venkata Ramana Anandula, Venkata Ramana Anandula, Vedam Ramprasad, Nalla Thambi Jeyabalan, Rohit Shetty, Arkasubhra Ghosh, Govindasamy Kumaramanickavel, ; Homozygosity Mapping of Keratoconus to 12p13.1 region: The Ideal Candidate Genes. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5304.
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Kertoconus (KC) a non-inflammatory disease results in progressively thinning of the cornea resulting to a conical shape causing refractive errors and visual disturbances. Linkage analyses on autosomal dominant and recessive families have identified various loci (16q22.3-23.1, 20q12, 3p14-q13, 5q14.3-q21.1, 15q 22.33-24.2, 17p13, regions on chromosomes 9, 4, 11, 12, 14) for KC, though so far no gene has been identified. Aim of this study is to map the gene for KC autosomal recessive consanguineous family of Asian Indian origin.
After ophthalmic evaluation including corneal topography and blood samples were collected for DNA analysis from a consanguineous KC family. Gene mapping was done using Affymetrix SNP 6.0 GeneChip using Homozygosity Mapper software. Using genome-wide study tools on the UCSC genome browser, we did further bioinformatic analyses of the chromosomal region identified.
Homozygosity data showed the susceptible chromosome region 12p13.1 associated with the SNP rs1544671. The region is linked to important disorders such as retinal cone dystrophy and inflammatory bowel disease (IBD). Genome browser analysis shows the SNP centeromeric to Ras related and estrogen regulated growth inhibitor (RERG) and Ras-related small GTP-binding proteins (ARHGDIB). However, genomewide ChIP-seq and ChIA-Pet analyses demonstrate few transcription factor binding sites in this area including CTCF and ER-alpha.
The homozygosity linked 12p13.1 region is rich in genes where the IBD could be suggestive of an inflammatory pathway involvement in the KC disease pathogenesis. IBD and retinal cone dystrophy could be indicative of an alternate pathway involvement in the KC disease pathogenesis. Although this region shows limited transcriptional activity, the presence of important growth inhibitory genes such as RERG, which has been shown to be tumor suppressors, may have important roles in KC pathophysiology. Sequencing the region should identify the causative gene in this family.
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