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PF Olson, AM Bajart, JJ Choi, ME Fini; Congenital Hereditary Stromal Dystrophy is not Caused by a Defect in the Lumican Gene . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2872.
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Purpose: Congenital Hereditary Stromal Dystrophy (CHSD) is a rare autosomal dominant disorder that manifests as bilateral neonatal corneal opacification. Confirmation of the diagnosis is made by electron microscopy of the diseased corneal tissue. Normal corneal collagen fibrils are small, uniform in diameter, and arranged in an almost crystalline-like manner. In CHSD, the corneal opacity is due to an abnormal size and arrangement of collagen fibrils in the posterior corneal stroma. We hypothesize that a defective gene that is involved in regulating corneal collagen fibrillogenesis causes CHSD. As this is a very rare disorder, the potential number of patients does not provide enough statistical power to determine the defective gene using classical linkage analysis. Therefore, we have chosen to use the candidate gene approach. The first gene we have examined is lumican, which is a leucine-rich proteoglycan involved in regulating corneal collagen fibrillogenesis. The lumican knockout mouse has a phenotype that is similar to CHSD. Methods:Penetrating keratoplasty was performed on each eye of an infant with bilateral "ground glass haze" corneal opacification. Corneal buttons removed from the proband upon penetrating keratoplasty were sectioned and processed with several standard pathology stains. Additionally a portion of each cornea was processed and examined by transmission electron microscopy. The six-generation family pedigree suggests autosomal dominant transmission of corneal clouding. Bloods were obtained from each of the two affecteds and two non-affecteds in the nuclear family, and genomic DNA was purified from each blood sample. The promoter, exons and splice-critical regions of each intron of the lumican gene were amplified by PCR from the gDNA of each family member and sequenced. Results:Transmission electron microscopy demonstrated that the collagen fibrils in the posterior corneal stroma were abnormally thin and disorganized, and confirmed the diagnosis of CHSD. Staining of corneal sections with Alcian Blue demonstrated that the tissue had an abnormally high level of muccopolysaccharides. Sequencing of the lumican gene in each family member did not reveal a polymorphism that co-segregated with the disease in this family. Conclusion:CHSD is not caused by a defect in the lumican gene. However, other genes whose products are involved in corneal collagen fibrillogenesis remain as candidates.
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