Macular corneal dystrophy (MCD) is an autosomal recessive corneal dystrophy which leads to progressive bilateral visual loss. The disease may begin during infancy or as late as the seventh decade of life, but vision usually becomes impaired during the second decade of life and worsens until penetrating keratoplasty is required to restore vision. A keratan sulfate like glycosaminoglycan accumulates in the cornea. Two types of MCD have been characterized and the location of the gene for both MCD type I and II 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. Blood has been collected from 205 individuals belonging to sixteen families of MCD. Over 110 markers have been screened for genomic localization and additional markers are being used in an ongoing attempt to localize the MCD gene. Once localization occurs, we will use selected YAC's and band specific microdissection libraries to develop highly polymorphic microsatellites that will closely flank these genes. We will use a variety of techniques including meiotic mapping and linkage disequilibrium to narrow the region containing this gene. The YAC megabase library will be used to construct a physical map spanning the disease locus. Coding regions will be identified through direct selection and if needed, exon amplification. As they become available candidate genes will be isolated and tested for mutations using PFGE, heteroduplex and SSCP. Once the defect is known we can begin to evaluate the basic physiologic mechanisms of the MCD gene.
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