Fine mapping of the Schnyder's crystalline corneal dystrophy locus.

Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Human Genetics (Impact Factor: 4.63). 06/2004; 114(6):594-600. DOI: 10.1007/s00439-004-1110-1
Source: PubMed

ABSTRACT Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant eye disease with a spectrum of clinical manifestations that may include bilateral corneal clouding, arcus lipoides, and anterior corneal crystalline cholesterol deposition. We have previously performed a genome-wide linkage analysis on two large Swede-Finn families and mapped the SCCD locus to a 16-cM interval between markers D1S2633 and D1S228 on chromosome 1p36. We have collected 11 additional families from Finland, Germany, Turkey, and USA to narrow the critical region for SCCD. Here, we have used haplotype analysis with densely spaced microsatellite markers in a total of 13 families to refine the candidate interval. A common disease haplotype was observed among the four Swede-Finn families indicating the presence of a founder effect. Recombination results from all 13 families refined the SCCD locus to 2.32 Mbp between markers D1S1160 and D1S1635. Within this interval, identity-by-state was present in all 13 families for two markers D1S244 and D1S3153, further refining the candidate region to 1.58 Mbp.

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    ABSTRACT: Schnyder crystalline corneal dystrophy (SCCD; MIM 121800) is a rare autosomal dominant disease characterized by an abnormal increase in cholesterol and phospholipid deposition in the cornea, leading to progressive corneal opacification. Although SCCD has been mapped to a genetic interval between markers D1S1160 and D1S1635, reclassification of a previously unaffected individual expanded the interval to D1S2667 and included nine additional genes. Three candidate genes that may be involved in lipid metabolism and/or are expressed in the cornea were analyzed. DNA samples were obtained from six families with clinically confirmed SCCD. Analysis of FRAP1, ANGPTL7, and UBIAD1 was performed by PCR-based DNA sequencing, to examine protein-coding regions, RNA splice junctions, and 5' untranslated region (UTR) exons. No disease-causing mutations were found in the FRAP1 or ANGPTL7 gene. A mutation in UBIAD1 was identified in all six families: Five families had the same N102S mutation, and one family had a G177R mutation. Predictions of the protein structure indicated that a prenyl-transferase domain and several transmembrane helices are affected by these mutations. Each mutation cosegregated with the disease in four families with DNA samples from both affected and unaffected individuals. Mutations were not observed in 100 control DNA samples (200 chromosomes). Nonsynonymous mutations in the UBIAD1 gene were detected in six SCCD families, and a potential mutation hot spot was observed at amino acid N102. The mutations are expected to interfere with the function of the UBIAD1 protein, since they are located in highly conserved and structurally important domains.
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    ABSTRACT: To report an unusual presentation of Schnyder's corneal crystalline dystrophy (SCCD), sharing the feature of central corneal mosaic opacities. Observational case report. A 51-year-old man and his family members were examined. Investigations included slit-lamp biomicroscopy, radiography of knee joint, plasma lipid level, and genotyping of the SCCD candidate region in chromosome 1p34.1-1p36. A symmetric, central, disciform, full-thickness opacity was seen in both corneas of the patient. The opacities appeared in a mosaic pattern, instead of collections of crystals or a diffuse haze as typically detected in SCCD. Small clumps of crystalline deposits and arcus lipoides were also observed. Systemically, hyperlipidemia and bilateral genu valgus were identified. He had 2 daughters, and both of them had bilateral corneal crystalline deposits and genu valgus. No other family members had findings suggesting SCCD. The genetic study demonstrated that all of the affected individuals shared a common haplotype within the region of previously reported SCCD locus. However, 1 unaffected sibling of the proband also had the same haplotype. Central corneal mosaic opacities may be another variant of SCCD.
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