Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval

Anthony J. Aldave, Vivek S. Yellore, Rosalind C. Vo, Khairidzan M. Kamal, Sylvia A. Rayner, Christopher L. Plaisier, Michael Chen, Mausam R. Damani, Michele N. Pham, Michael B. Gorin, Eric Sobel, Jeanette Papp

Research output: Contribution to journalArticle

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Abstract

PURPOSE:: Posterior polymorphous corneal dystrophy (PPCD) is an autosomal-dominant disorder of the corneal endothelium associated with visually significant corneal edema and glaucoma. Statistical genetic analysis of 4 families with PPCD has demonstrated linkage to a 2.4 cM common support interval on chromosome 20 bordered by the markers D20S182 and D20S139. We sought to identify the genetic basis of PPCD linked to chromosome 20 (PPCD1) by screening the 26 positional candidate genes between these markers in a family previously mapped to the PPCD1 region. METHODS:: The coding regions of the 26 positional candidate genes mapped to the common PPCD1 support interval were amplified and sequenced in affected and unaffected individuals from a family previously linked to the PPCD1 locus. Nine other genes positioned just outside of the common PPCD1 support interval but within the autosomal-dominant congenital hereditary endothelial dystrophy interval were also screened. RESULTS:: Four DNA sequence variants in 3 of the positional candidate genes demonstrated complete segregation with the affected phenotype: p.Thr109Thr (rs6111803) in OVOL2, p.Arg56Gln (novel variant-RPSnovel) in RPS19P1, and p.Thr85Thr (rs1053834) and p.Pro99Ser (rs1053839) in C20orf79. Each of these 4 sequence variants demonstrated significant linkage with the affected phenotype in this family (P = 2.5 × 10 for RPSnovel, rs1053834 and rs1053839; P = 8.6 × 10 for rs6111803). However, we also identified each of these 4 sequence variants in ≥9% unaffected control individuals. The haplotype on which the disease-causing mutation is segregating was found to have a population frequency of 4.2% in the CEPH HapMap trios. Although a number of other previously described and novel single nucleotide polymorphisms were identified in the 35 positional candidate genes located within the PPCD1 and congenital hereditary endothelial dystrophy intervals, none segregated with the affected phenotype. CONCLUSIONS:: We report the absence of a presumed pathogenic coding region mutation in the common PPCD1 support interval. Although minor alleles of 4 single nucleotide polymorphisms were identified that segregated with the affected phenotype, the relatively high frequency of each minor allele in the general population indicates that none is a candidate for the causal variant for PPCD. Instead, the causal variant is most likely a coding region deletion or a variant in a noncoding region of the PPCD1 common support interval.

Original languageEnglish (US)
Pages (from-to)801-807
Number of pages7
JournalCornea
Volume28
Issue number7
DOIs
StatePublished - Sep 28 2009

Fingerprint

Mutation
Chromosomes, Human, Pair 20
Phenotype
Genes
Single Nucleotide Polymorphism
Alleles
HapMap Project
Corneal Edema
Corneal Endothelium
Glaucoma
Haplotypes
Population
Corneal Dystrophy, Posterior Polymorphous, 1

All Science Journal Classification (ASJC) codes

  • Ophthalmology

Cite this

Aldave, A. J., Yellore, V. S., Vo, R. C., Kamal, K. M., Rayner, S. A., Plaisier, C. L., ... Papp, J. (2009). Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval. Cornea, 28(7), 801-807. https://doi.org/10.1097/ICO.0b013e31819672fb
Aldave, Anthony J. ; Yellore, Vivek S. ; Vo, Rosalind C. ; Kamal, Khairidzan M. ; Rayner, Sylvia A. ; Plaisier, Christopher L. ; Chen, Michael ; Damani, Mausam R. ; Pham, Michele N. ; Gorin, Michael B. ; Sobel, Eric ; Papp, Jeanette. / Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval. In: Cornea. 2009 ; Vol. 28, No. 7. pp. 801-807.
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abstract = "PURPOSE:: Posterior polymorphous corneal dystrophy (PPCD) is an autosomal-dominant disorder of the corneal endothelium associated with visually significant corneal edema and glaucoma. Statistical genetic analysis of 4 families with PPCD has demonstrated linkage to a 2.4 cM common support interval on chromosome 20 bordered by the markers D20S182 and D20S139. We sought to identify the genetic basis of PPCD linked to chromosome 20 (PPCD1) by screening the 26 positional candidate genes between these markers in a family previously mapped to the PPCD1 region. METHODS:: The coding regions of the 26 positional candidate genes mapped to the common PPCD1 support interval were amplified and sequenced in affected and unaffected individuals from a family previously linked to the PPCD1 locus. Nine other genes positioned just outside of the common PPCD1 support interval but within the autosomal-dominant congenital hereditary endothelial dystrophy interval were also screened. RESULTS:: Four DNA sequence variants in 3 of the positional candidate genes demonstrated complete segregation with the affected phenotype: p.Thr109Thr (rs6111803) in OVOL2, p.Arg56Gln (novel variant-RPSnovel) in RPS19P1, and p.Thr85Thr (rs1053834) and p.Pro99Ser (rs1053839) in C20orf79. Each of these 4 sequence variants demonstrated significant linkage with the affected phenotype in this family (P = 2.5 × 10 for RPSnovel, rs1053834 and rs1053839; P = 8.6 × 10 for rs6111803). However, we also identified each of these 4 sequence variants in ≥9{\%} unaffected control individuals. The haplotype on which the disease-causing mutation is segregating was found to have a population frequency of 4.2{\%} in the CEPH HapMap trios. Although a number of other previously described and novel single nucleotide polymorphisms were identified in the 35 positional candidate genes located within the PPCD1 and congenital hereditary endothelial dystrophy intervals, none segregated with the affected phenotype. CONCLUSIONS:: We report the absence of a presumed pathogenic coding region mutation in the common PPCD1 support interval. Although minor alleles of 4 single nucleotide polymorphisms were identified that segregated with the affected phenotype, the relatively high frequency of each minor allele in the general population indicates that none is a candidate for the causal variant for PPCD. Instead, the causal variant is most likely a coding region deletion or a variant in a noncoding region of the PPCD1 common support interval.",
author = "Aldave, {Anthony J.} and Yellore, {Vivek S.} and Vo, {Rosalind C.} and Kamal, {Khairidzan M.} and Rayner, {Sylvia A.} and Plaisier, {Christopher L.} and Michael Chen and Damani, {Mausam R.} and Pham, {Michele N.} and Gorin, {Michael B.} and Eric Sobel and Jeanette Papp",
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Aldave, AJ, Yellore, VS, Vo, RC, Kamal, KM, Rayner, SA, Plaisier, CL, Chen, M, Damani, MR, Pham, MN, Gorin, MB, Sobel, E & Papp, J 2009, 'Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval', Cornea, vol. 28, no. 7, pp. 801-807. https://doi.org/10.1097/ICO.0b013e31819672fb

Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval. / Aldave, Anthony J.; Yellore, Vivek S.; Vo, Rosalind C.; Kamal, Khairidzan M.; Rayner, Sylvia A.; Plaisier, Christopher L.; Chen, Michael; Damani, Mausam R.; Pham, Michele N.; Gorin, Michael B.; Sobel, Eric; Papp, Jeanette.

In: Cornea, Vol. 28, No. 7, 28.09.2009, p. 801-807.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Exclusion of positional candidate gene coding region mutations in the common posterior polymorphous corneal dystrophy 1 candidate gene interval

AU - Aldave, Anthony J.

AU - Yellore, Vivek S.

AU - Vo, Rosalind C.

AU - Kamal, Khairidzan M.

AU - Rayner, Sylvia A.

AU - Plaisier, Christopher L.

AU - Chen, Michael

AU - Damani, Mausam R.

AU - Pham, Michele N.

AU - Gorin, Michael B.

AU - Sobel, Eric

AU - Papp, Jeanette

PY - 2009/9/28

Y1 - 2009/9/28

N2 - PURPOSE:: Posterior polymorphous corneal dystrophy (PPCD) is an autosomal-dominant disorder of the corneal endothelium associated with visually significant corneal edema and glaucoma. Statistical genetic analysis of 4 families with PPCD has demonstrated linkage to a 2.4 cM common support interval on chromosome 20 bordered by the markers D20S182 and D20S139. We sought to identify the genetic basis of PPCD linked to chromosome 20 (PPCD1) by screening the 26 positional candidate genes between these markers in a family previously mapped to the PPCD1 region. METHODS:: The coding regions of the 26 positional candidate genes mapped to the common PPCD1 support interval were amplified and sequenced in affected and unaffected individuals from a family previously linked to the PPCD1 locus. Nine other genes positioned just outside of the common PPCD1 support interval but within the autosomal-dominant congenital hereditary endothelial dystrophy interval were also screened. RESULTS:: Four DNA sequence variants in 3 of the positional candidate genes demonstrated complete segregation with the affected phenotype: p.Thr109Thr (rs6111803) in OVOL2, p.Arg56Gln (novel variant-RPSnovel) in RPS19P1, and p.Thr85Thr (rs1053834) and p.Pro99Ser (rs1053839) in C20orf79. Each of these 4 sequence variants demonstrated significant linkage with the affected phenotype in this family (P = 2.5 × 10 for RPSnovel, rs1053834 and rs1053839; P = 8.6 × 10 for rs6111803). However, we also identified each of these 4 sequence variants in ≥9% unaffected control individuals. The haplotype on which the disease-causing mutation is segregating was found to have a population frequency of 4.2% in the CEPH HapMap trios. Although a number of other previously described and novel single nucleotide polymorphisms were identified in the 35 positional candidate genes located within the PPCD1 and congenital hereditary endothelial dystrophy intervals, none segregated with the affected phenotype. CONCLUSIONS:: We report the absence of a presumed pathogenic coding region mutation in the common PPCD1 support interval. Although minor alleles of 4 single nucleotide polymorphisms were identified that segregated with the affected phenotype, the relatively high frequency of each minor allele in the general population indicates that none is a candidate for the causal variant for PPCD. Instead, the causal variant is most likely a coding region deletion or a variant in a noncoding region of the PPCD1 common support interval.

AB - PURPOSE:: Posterior polymorphous corneal dystrophy (PPCD) is an autosomal-dominant disorder of the corneal endothelium associated with visually significant corneal edema and glaucoma. Statistical genetic analysis of 4 families with PPCD has demonstrated linkage to a 2.4 cM common support interval on chromosome 20 bordered by the markers D20S182 and D20S139. We sought to identify the genetic basis of PPCD linked to chromosome 20 (PPCD1) by screening the 26 positional candidate genes between these markers in a family previously mapped to the PPCD1 region. METHODS:: The coding regions of the 26 positional candidate genes mapped to the common PPCD1 support interval were amplified and sequenced in affected and unaffected individuals from a family previously linked to the PPCD1 locus. Nine other genes positioned just outside of the common PPCD1 support interval but within the autosomal-dominant congenital hereditary endothelial dystrophy interval were also screened. RESULTS:: Four DNA sequence variants in 3 of the positional candidate genes demonstrated complete segregation with the affected phenotype: p.Thr109Thr (rs6111803) in OVOL2, p.Arg56Gln (novel variant-RPSnovel) in RPS19P1, and p.Thr85Thr (rs1053834) and p.Pro99Ser (rs1053839) in C20orf79. Each of these 4 sequence variants demonstrated significant linkage with the affected phenotype in this family (P = 2.5 × 10 for RPSnovel, rs1053834 and rs1053839; P = 8.6 × 10 for rs6111803). However, we also identified each of these 4 sequence variants in ≥9% unaffected control individuals. The haplotype on which the disease-causing mutation is segregating was found to have a population frequency of 4.2% in the CEPH HapMap trios. Although a number of other previously described and novel single nucleotide polymorphisms were identified in the 35 positional candidate genes located within the PPCD1 and congenital hereditary endothelial dystrophy intervals, none segregated with the affected phenotype. CONCLUSIONS:: We report the absence of a presumed pathogenic coding region mutation in the common PPCD1 support interval. Although minor alleles of 4 single nucleotide polymorphisms were identified that segregated with the affected phenotype, the relatively high frequency of each minor allele in the general population indicates that none is a candidate for the causal variant for PPCD. Instead, the causal variant is most likely a coding region deletion or a variant in a noncoding region of the PPCD1 common support interval.

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