Macular corneal dystrophy (MCD) is a rare, autosomal recessive ocular storage disease which leads to progressive bilateral visual loss. Clinical progression of the disease usually causes visual impairment during the second decade of life and generally worsens until penetrating keratoplasty (cornea transplantation) is required to restore vision usually by the fourth decade of life. A keratan sulfate like glycosaminoglycan accumulates in the cornea. The location of the gene for MCD is unknown and no presymptomatic diagnostic test is available to individuals who are at risk. Nor is there a reliable form of carrier detection. The objective of the proposed research is to define the genomic location of the MCD gene(s) while concurrently attempting to characterize the storage substance. Participants will be selected from a registry of affected individuals and their unaffected relatives maintained by the Principal Investigator. Blood samples will be obtained from affected individuals, their parents, and siblings to establish lymphoblastoid cell lines as permanent sources of DNA. In addition, serum will be tested for a specific epitope of sulfated keratan sulfate which is known to be markedly reduced in many affected individuals. Linkage analysis of MCD with restriction fragment length polymorphisms randomly located throughout the genome as well as candidate genes that become available will be performed using state-of-the-art statistical methodology. The establishment of a linkage relationship and identification of the chromosomal location are the first steps in identifying the gene. Fine gene mapping, gene expression, the nature of the abnormal accumulates, and its mechanism of generation may then be possible. In addition establishment of linkage relationships may clarify the possibility of genetic heterogeneity in this disorder. These developments will lead to a method of presymptomatic diagnosis of MCD and detection of carriers of the MCD gene. Eventually the work may lead to an alternative means of treating MCD when further techniques of genetic engineering become available.
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