Mutations in the UBIAD1 Gene, Encoding a Potential Prenyltransferase, Are Causal for Schnyder Crystalline Corneal Dystrophy

Orr, Andrew; Dubé, Marie‐Pierre; Marcadier, Julien L.; Jiang, Haiyan; Federico, Antonio; George, Stanley; Seamone, Christopher; Andrews, David Q.; Dubord, Paul; Holland, Simon; Provost, Sylvie; Mongrain, Vanessa; Evans, Susan C.; Higgins, Brent; Bowman, Sharen; Guernsey, Duane L.; Samuels, Mark E.

doi:10.1371/journal.pone.0000685

“…The locations of the mutations identified in this as well as two prior publications [Orr et al, 2007;Weiss et al, 2007] revealed several clusters of mutations (Fig. 4A).…”

Section: Analysis Of the Potential Consequences Of The Mutationssupporting

confidence: 84%

“…Many of the mutations reported in this and prior studies [Orr et al, 2007;Weiss et al, 2007] were nonconservative amino acid substitutions. There were dramatic size and/or shape differences between the reference sequence and mutant amino acids in 7/8 mutations (N102S, D118G, L121F, S171P, T175I, G177R, G186R).…”

Section: Analysis Of the Potential Consequences Of The Mutationssupporting

confidence: 57%

“…DNA sequencing revealed mutations in all 30 affected members and none of the six unaffected members from all 14 families (Table I). Eight distinct mutations were found including two previously described mutations, N102S [Orr et al, 2007;Weiss et al, 2007], G177R and T175I [Orr et al, 2007] in exon 1. Novel mutations in exon 1 included L121F (families BB3 and O), D118G (family H), and S171P (family K1).…”

Section: Resultsmentioning

confidence: 89%

“…These are circled and identified as loops 1, 2, or 3. Each loop contains an aqueous portion of the protein and Orr et al [2007]. The location of the S75F SNP is indicated by a red arrowhead Orr et al, 2007].…”

Section: Analysis Of the Potential Consequences Of The Mutationsmentioning

confidence: 99%

“…Recently, we described that mutations in the UBIAD1 gene resulted in SCCD when we reported six families with two different mutations, N102S and G177R. Orr et al [2007] independently described five SCCD families with five distinct mutations: N102S, D112G, R119G, T175I, and N232S.…”

Section: Introductionmentioning

confidence: 99%

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Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function

Weiss

¹

,

Kruth

²

,

Kuivaniemi

³

et al. 2008

American J of Med Genetics Pt A

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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

show abstract

Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function

Weiss

¹

,

Kruth

²

,

Kuivaniemi

³

et al. 2008

American J of Med Genetics Pt A

View full text Add to dashboard Cite

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.

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The sumLINK statistic for genetic linkage analysis in the presence of heterogeneity

Christensen

¹

,

Knight

²

,

Camp

³

2009

Genetic Epidemiology

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We present the “sumLINK” statistic—the sum of multipoint LOD scores for the subset of pedigrees with nominally significant linkage evidence at a given locus—as an alternative to common methods to identify susceptibility loci in the presence of heterogeneity. We also suggest the “sumLOD” statistic (the sum of positive multipoint LOD scores) as a companion to the sumLINK. SumLINK analysis identifies genetic regions of extreme consistency across pedigrees without regard to negative evidence from unlinked or uninformative pedigrees. Significance is determined by an innovative permutation procedure based on genome shuffling that randomizes linkage information across pedigrees. This procedure for generating the empirical null distribution may be useful for other linkage-based statistics as well. Using 500 genome-wide analyses of simulated null data, we show that the genome shuffling procedure results in the correct type 1 error rates for both the sumLINK and sumLOD. The power of the statistics was tested using 100 sets of simulated genome-wide data from the alternative hypothesis from GAW13. Finally, we illustrate the statistics in an analysis of 190 aggressive prostate cancer pedigrees from the International Consortium for Prostate Cancer Genetics, where we identified a new susceptibility locus. We propose that the sumLINK and sumLOD are ideal for collaborative projects and meta-analyses, as they do not require any sharing of identifiable data between contributing institutions. Further, loci identified with the sumLINK have good potential for gene localization via statistical recombinant mapping, as, by definition, several linked pedigrees contribute to each peak.

show abstract

Mutations in the UBIAD1 Gene, Encoding a Potential Prenyltransferase, Are Causal for Schnyder Crystalline Corneal Dystrophy

Cited by 117 publications

References 43 publications

Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function

Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function

Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function

The sumLINK statistic for genetic linkage analysis in the presence of heterogeneity

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