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.
"Aldave et al.  and Yellore et al.  have reported sequencing of all annotated genes within the 2.32 Mbp interval, finding no pathogenic mutations and tentatively excluding them as causing SCCD, a finding proposed to result from locus heterogeneity, mutations within promoter or untranslated regions, the presence of an unannotated gene, or an error in the assignment of the candidate locus for SCCD due to misclassification of disease status in family members. Indeed, reanalysis of the pedigrees reported in an article by Theendakara et al.  showed a misclassification in one individual. The family which this individual belonged to had been used to define the centromeric boundary of the candidate interval at D1S1635. "
[Show abstract][Hide abstract] ABSTRACT: To identify the molecular defect causing Schnyder crystalline corneal dystrophy (SCCD) in a Chinese family with bilateral corneal abnormalities.
The Chinese SCCD family was subjected to a complete ophthalmic examination that included slit-lamp examination and slit-lamp photography to assess and document the crystalline deposits and arcus lipoides. In vivo laser scanning confocal microscopy and Fourier-domain OCT were also performed on both eyes of SCCD patients. Blood samples were taken for subsequent genetic analysis. The two coding exons of the UbiA prenyltransferase domain-containing protein 1 (UBIAD1) gene were screened for mutations by direct sequencing.
We report on a novel heterozygous mutation of UBIAD1, G98S, in two patients with SCCD. The identified molecular defect cosegregates with the disease and is not found in 50 unaffected individuals. Morphological evaluation on SCCD by in vivo laser scanning confocal microscopy and Fourier-domain OCT highlighted pathological observations at the level of Bowman's membrane and anterior stroma.
The newly identified mutation expands the spectrum of mutations in UBIAD1 that may cause pathological corneal cholesterol deposition. Observations by in vivo laser scanning confocal microscopy and Fourier-domain OCT were consistent with the previous histopathologic descriptions of SCCD.
"The recruitment efforts which spanned from 1987 to the present have been described in prior publications [Shearman et al., 1996; Theendakara et al., 2004] with Institutional Review Board approval of the study obtained from University of Massachusetts Medical Center from 1992 to 1995 and subsequently from Wayne State University to the present. Written informed consent was obtained from all adults and the parents of minors under research tenets of the Declaration of Helsinki. "
[Show abstract][Hide abstract] ABSTRACT: Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive corneal opacification resulting from abnormal deposition of cholesterol and phospholipids. Recently, six different mutations on the UBIAD1 gene on chromosome 1p36 were found to result in SCCD. The purpose of this article is to further characterize the mutation spectrum of SCCD and identify structural and functional consequences for UBIAD1 protein activity. DNA sequencing was performed on samples from 36 individuals from 14 SCCD families. One affected individual was African American and SCCD has not been previously reported in this ethnic group. We identified UBIAD1 mutations in all 14 families which had 30 affected and 6 unaffected individuals. Eight different UBIAD1 mutations, 5 novel (L121F, D118G, and S171P in exon 1, G186R and D236E in exon 2) were identified. In four families with DNA samples from both affected and unaffected individuals, the D118G, G186R, T175I, and G177R mutations cosegregated with SCCD. In combination with our previous report, we have identified the genetic mutation in UBIAD1 in 20 unrelated families with 10 (including 5 reported here), having the N102S mutation. The results suggest that N102S may be a mutation hot spot because the affected families were unrelated including Caucasian and Asian individuals. There was no genotype phenotype correlation except for the T175I mutation which demonstrated prominent diffuse corneal haze, typically without corneal crystals. Protein analysis revealed structural and functional implications of SCCD mutations which may affect UBIAD1 function, ligand binding and interaction with binding partners, like apo E.
American Journal of Medical Genetics Part A 04/2008; 146(7):952-64. DOI:10.1002/ajmg.a.32328 · 2.16 Impact Factor
"The recombinant interval defined by our family 105 overlaps with, but is offset slightly centromeric to that previously defined. The location of gene UBIAD1 itself is consistent with chromosomal haplotypes in 70 of the 71 affected individuals from 13 families described in the previous study, with the exception of one recombinant individual, affected III:4 in family 9. "
[Show abstract][Hide abstract] ABSTRACT: Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive opacification of the cornea resulting from the local accumulation of lipids, and associated in some cases with systemic dyslipidemia. Although previous studies of the genetics of SCCD have localized the defective gene to a 1.58 Mbp interval on chromosome 1p, exhaustive sequencing of positional candidate genes has thus far failed to reveal causal mutations. We have ascertained a large multigenerational family in Nova Scotia affected with SCCD in which we have confirmed linkage to the same general area of chromosome 1. Intensive fine mapping in our family revealed a 1.3 Mbp candidate interval overlapping that previously reported. Sequencing of genes in our interval led to the identification of five putative causal mutations in gene UBIAD1, in our family as well as in four other small families of various geographic origins. UBIAD1 encodes a potential prenyltransferase, and is reported to interact physically with apolipoprotein E. UBIAD1 may play a direct role in intracellular cholesterol biochemistry, or may prenylate other proteins regulating cholesterol transport and storage.
PLoS ONE 02/2007; 2(8):e685. DOI:10.1371/journal.pone.0000685 · 3.23 Impact Factor
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