El-Ashry, Mohamed Farouk; (2001) Molecular genetics of corneal dystrophy. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Corneal dystrophies are inherited disorders characterised by progressive accumulation of deposits in the cornea causing visual impairment. They occur in either an autosomal dominant or recessive form and are usually manifested in the first few decades of life. The present classification is solely based on the layer or layers of the comea involved. This study aimed at better understanding of the underlying molecular basis of such disorders via linkage to specific chromosomal loci and then mutation screening of the disease genes by means of amplification of the genomic DNA using polymerase chain reaction and then sequencing and restriction enzyme digest analysis. A family with a combined comea plana and microphthalmia phenotype was mapped to the autosomal recessive comea plana (CNA2) locus on 12q21. A novel mutation in KERA gene (CNA2) has also been identified. The phenotype described is wider than that previously reported for KERA mutations and represents the first description of a stmctural protein causing microphthalmia. Mutation screening of a new carbohydrate sulfotransferase 6 gene (CHST6) in 5 families with autosomal recessive macular comeal dystrophy (MCD) type I has revealed 6 novel missense mutations, 4 homozygous and 2 compound heterozygous. This study provides further evidence that CHST6 is the MCD gene and the loss of gene function by these mutations may result in production of abnormal keratan sulfate, which would account for the MCD phenotype. Analysis of a human transforming growth factor-β-induced gene (BIGH3) in 36 patients with lattice comeal dystrophy type I (LCDI), Avellino comeal dystrophy (ACD), granular comeal dystrophy (GCD), and Reis-Bucklers' comeal dystrophy (RBCD) has revealed 4 heterozygous missense mutations. In conclusion, molecular genetics may provide a more accurate basis for the diagnosis and classification of comeal dystrophies. This work contributes to our understanding of the role of specific genes in corneal transparency and may help to identify novel therapeutic approaches for these dystrophies that cause significant visual impairment.

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