Abstract
Purpose:
Keratoconus (KC) is the most common corneal dystrophy with a prevalence rate of 0.05% of people in the USA, even though it is classified under rare diseases. Indian subcontinent has a four fold greater incidence of the disease. The precise etiopathogenesis of KC is unclear. However, strong family history and large autosomal dominant and few recessive pedigrees' linkage with the disorder has shown that genetics is one of the leading causes for KC. This study is to map the gene that is causative of the disease in a consanguineous autosomal recessive family.
Methods:
The family members underwent detailed ophthalmic evaluation including corneal topography. The members of the consanguineous family were bled for DNA with all ethical considerations. The samples were run on genomewide Affymetrix SNP 6.0 GeneChip and the data were analyzed using the Homozygosity Mapper software. Further bioinformatic analyses of the chromosomal region identified was done by using genome-wide study tools on the UCSC genome browser.
Results:
Homozygosity mapping reveals the causative region in this family on chromosome 14q11.2 and associated with the SNP rs3811259. Genome browser shows the SNP centeromeric to TCR- alpha gene (TCRA). The region is linked to inflammatory bowel disease (IBD) and also to several transcription factor and histone deacetylase binding sites such as FOXA1 (estrogen receptor), CTCF (11-zinc finger protein) etc and histone modifier binding sites like HDAC2, p300 etc. A few keratoconus related candidate genes like APEX1 (multifunctional DNA repair enzyme), CIDE-B (cell death-inducing DFFA-like effector b) are in this region.
Conclusions:
There are the few candidate genes for KC in the homozygously linked 14q11.2 region. IBD could be indicative of an inflammatory pathway involvement in the KC disease pathogenesis. Furthermore, the presence of prevalence of transcription factor binding sites as per genome-wide ChIP-seq data and histone modification marks suggests this region to be transcriptionally active. Interestingly, APEX1, a DNA repair gene and CIDE-B, which has a role in apoptosis, is highly expressed in the KC cornea indicating the involvement in non-canonical roles. Thus, this chromosomal region may have the key causative role gene for KC etiopathogenesis.
Keywords: 574 keratoconus