Ebenezer, Neil David; (2003) Corneal dystrophies: Molecular genetic studies and mutational analysis of candidate genes. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Corneal dystrophies are a clinically heterogeneous group of rare inherited ocular disorders that often result in a reduction in visual acuity. These dystrophies can be inherited as either an autosomal dominant or autosomal recessive trait, which can affect one or more layers of the cornea. Autosomal dominant congenital hereditary endothelial dystrophy (CHED1) is a severe disease, which affects the corneal endothelium. The largest reported family with CHED1 was used to identify the locus for the disease on chromosome 20 using linkage analysis. The CHED1 disease interval was refined to 2.7 cM on chromosome 20p11.2 flanked by the markers D20S48 and D20S471. A physical map was created using a YAC and PAC contig to anchor sequence tagged sites (STSs) and expressed tagged sites (ESTs) to the CHED1 interval. The genes, destrin, VSX1 and the cystatin gene cluster were excluded as candidates for CHED1 (Chapter 3). The autosomal recessive form of congenital hereditary endothelial dystrophy (CHED2) was previously localised to an 8 cM region on chromosome 20p13. A positional candidate gene approach was adopted to identify the causative gene for CHED2. In collaboration with the Chromosome 20 group at the Sanger Institute, a PAC and BAC contig was created spanning the 3.7 Mb disease interval. Analysis of the genomic sequence predicted 62 genes or transcripts within this region. A small Pakistani family, which had previously been linked to the locus on 20p13, was used to screen CDS2 for mutations (Chapter 4). Granular corneal dystrophy (CDGG1) is an autosomal dominant disease characterised by non amyloid deposits in the stroma. A British CDGG1 pedigree was linked to chromosome 5q31-33 flanked by the markers D5S421 and D5S399. YACs from the CEPH YAC library were used to create a physical map of the disease interval. [beta]ig-H3, previously identified as the causative gene for a number of stromal dystrophies, was screened in this pedigree and a mutation in exon 12 was identified (Chapter 5). Cornea plana is characterised by a flattened corneal surface and can be inherited as a mild autosomal dominant disease (CNA1) or a more severe autosomal recessive form (CNA2). A small Hispanic family with CNA2 was ascertained and screened for mutations in the keratocan gene. A homozygous mutation in exon 2 was identified (Chapter 6). This molecular genetic study of both recessive and dominant disease has contributed to our knowledge of corneal dystrophies.

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