Schnyder's crystalline corneal dystrophy (SCCD; OMIM number 121800) an autosomal dominant disease in which there is abnormal deposition of cholesterol and lipid in the cornea resulting in opacification and loss of vision. The dystrophy may manifest early in life and clinical appearance includes central corneal opacification, subepithelial cholesterol deposition, mid- peripheral stromal opacification and/or arcus lipoides. SCCD has been mapped to the chromosome 1p36.2-p36.3 with a maximum multipoint lod score of 8.48 in the interval between genetic markers D1S214 and D1S503 using two large Swede-Finn kindreds from Massachusetts. Haplotype analysis suggested that the SCCD gene is located in the 16 cM interval between markers D1S2663 and D1S228. In the present application, we propose to identify the gene which is responsible for SCCD. To accomplish this goal we will: 1) continue to fine map the disease locus with several additional families that display SCCD. The new and the original two large families will also be typed for additional polymorphic markers that map in the disease interval to help narrow the locus; 2) examine potential candidate genes that map to the refined disease interval to search for polymorphisms and/or mutations that may give rise to SCCD. Sequence polymorphisms and/or mutations will be examined for co-segregation with SCCD in the families (NOTE! The defined region will be most likely completely sequenced by the time the grant is funded making it unnecessary to screen cDNA libraries for extended sequence information. Also, this means that the mutation screening can be accomplished by using genomic DNA as a starting material. The term """"""""potential candidate"""""""" here means that we will first search for mutations in those genes whose function is known and which are biologically relevant candidates. If no mutations are found in these genes the search will continue to genes with unknown function that are located in the defined candidate interval); and 3) use microarray expression profiling to identify differences in the expression levels of cDNAs mapped to the candidate interval in corneal tissue samples between SCCD patients and controls. Identification of the gene at fault and the specific mutations responsible for SCCD phenotype will not only afford increased understanding about SCCD but may provide insight into lipid metabolism in the cornea and elsewhere.
