Advances in the molecular genetics of corneal dystrophies

PURPOSE: To improve our understanding of the role of specific genes on corn eal transparency through a review of linkage to specific chromosomal loci a nd the identification of the mutant genes dealing with the corneal dystroph ies. METHOD: Relevant recent literature on the corneal dystrophies is reviewed, RESULTS: Molecular genetic studies of the corneal dystrophies suggest that genes on at least 10 human chromosomes are involved in the maintenance of c orneal transparency (chromosomes 1, 5, 9, 10, 12, 16, 17, 20, 21, and X). W ithin the 10 chromosomes to which corneal dystrophies have been mapped, spe cific genetic mutations in seven genes (GSN, BIGH3, KRT3, KRT12, MSS1, GLA, and ARSC1) have been identified in 15 corneal dystrophies. Some corneal dy strophies that are considered distinct clinicopathologic entities are actua lly caused by different mutations in the same gene. For example, lattice dy strophy types I and IIIA, granular corneal dystrophy types I, II (Avellino dystrophy), and III (Reis-Bucklers dystrophy), and Thiel-Behnke corneal dys trophy are the result of mutations in BIGH3. Mutations in three genes (GSN, BIGH3, MSS1) are associated with amyloid deposition in the cornea. A gene for keratoconus has been mapped to chromosome 21, which:is noteworthy becau se of the established association of keratoconus in Down syndrome (trisomy 21). CONCLUSION: Recent genetic studies on the corneal dystrophies provide insig ht into some of these disorders at a basic molecular level. Some corneal dy strophies that were previously believed to be distinct clinicopathologic en tities are closely related at the molecular level with the different phenot ypes resulting from distinct mutations in the same gene, This new knowledge is leading to a revised classification of the corneal dystrophies and to t he development of animal models of corneal dystrophies. The latter will lea d to a better understanding of the pathogenesis of the disorders and hence to novel therapeutic approaches to those dystrophies that cause significant visual impairment, Research of this nature is only in its infancy. (C) 199 9 by Elsevier Science Inc. All rights reserved.