A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions

Verity F. Oliver, Katherine A. van Bysterveldt, Murray Cadzow, Bernhard Steger, Vito Romano, David Markie, Alex W. Hewitt, David A. Mackey, Colin Willoughby, Trevor Sherwin, Philip S. Crosier, Charles N. McGhee, Andrea L. Vincent

    Research output: Contribution to journalArticle

    12 Citations (Scopus)

    Abstract

    PURPOSE:Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.DESIGN:Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.PARTICIPANTS:Four ERED families, including 28 affected and 17 unaffected individuals.METHODS:HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle-niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.MAIN OUTCOME MEASURES:Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.RESULTS:Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562-112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ-TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.CONCLUSIONS:The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.
    LanguageEnglish
    Pages709-722
    JournalOphthalmology: Journal of the American Academy of Ophthalmology
    Volume123
    Issue number4
    DOIs
    Publication statusAccepted/In press - 5 Dec 2015

    Fingerprint

    Zebrafish
    Mutation
    Exome
    Cornea
    Morpholinos
    Microarray Analysis
    In Situ Hybridization
    Proteins
    Embryonic Structures
    Immunohistochemistry
    Epithelial Recurrent Erosion Dystrophy
    Epidermolysis Bullosa
    Gene Knockdown Techniques
    Chromosomes, Human, Pair 12
    Corneal Epithelium
    Pedigree
    DNA Sequence Analysis
    Genes
    Genotype
    Phenotype

    Keywords

    • corneal dystrophy
    • collagen XVII
    • epithelial recurrent erosion dystrophy (ERED)

    Cite this

    Oliver, V. F., van Bysterveldt, K. A., Cadzow, M., Steger, B., Romano, V., Markie, D., ... Vincent, A. L. (Accepted/In press). A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions. Ophthalmology: Journal of the American Academy of Ophthalmology, 123(4), 709-722. https://doi.org/10.1016/j.ophtha.2015.12.008
    Oliver, Verity F. ; van Bysterveldt, Katherine A. ; Cadzow, Murray ; Steger, Bernhard ; Romano, Vito ; Markie, David ; Hewitt, Alex W. ; Mackey, David A. ; Willoughby, Colin ; Sherwin, Trevor ; Crosier, Philip S. ; McGhee, Charles N. ; Vincent, Andrea L. / A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions. In: Ophthalmology: Journal of the American Academy of Ophthalmology. 2015 ; Vol. 123, No. 4. pp. 709-722.
    @article{496c28028dd64ed496a67162da95a164,
    title = "A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions",
    abstract = "PURPOSE:Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.DESIGN:Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.PARTICIPANTS:Four ERED families, including 28 affected and 17 unaffected individuals.METHODS:HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle-niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.MAIN OUTCOME MEASURES:Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.RESULTS:Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562-112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ-TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.CONCLUSIONS:The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.",
    keywords = "corneal dystrophy, collagen XVII, epithelial recurrent erosion dystrophy (ERED)",
    author = "Oliver, {Verity F.} and {van Bysterveldt}, {Katherine A.} and Murray Cadzow and Bernhard Steger and Vito Romano and David Markie and Hewitt, {Alex W.} and Mackey, {David A.} and Colin Willoughby and Trevor Sherwin and Crosier, {Philip S.} and McGhee, {Charles N.} and Vincent, {Andrea L.}",
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    language = "English",
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    Oliver, VF, van Bysterveldt, KA, Cadzow, M, Steger, B, Romano, V, Markie, D, Hewitt, AW, Mackey, DA, Willoughby, C, Sherwin, T, Crosier, PS, McGhee, CN & Vincent, AL 2015, 'A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions', Ophthalmology: Journal of the American Academy of Ophthalmology, vol. 123, no. 4, pp. 709-722. https://doi.org/10.1016/j.ophtha.2015.12.008

    A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions. / Oliver, Verity F.; van Bysterveldt, Katherine A.; Cadzow, Murray; Steger, Bernhard; Romano, Vito; Markie, David; Hewitt, Alex W.; Mackey, David A.; Willoughby, Colin; Sherwin, Trevor; Crosier, Philip S.; McGhee, Charles N.; Vincent, Andrea L.

    In: Ophthalmology: Journal of the American Academy of Ophthalmology, Vol. 123, No. 4, 05.12.2015, p. 709-722.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions

    AU - Oliver, Verity F.

    AU - van Bysterveldt, Katherine A.

    AU - Cadzow, Murray

    AU - Steger, Bernhard

    AU - Romano, Vito

    AU - Markie, David

    AU - Hewitt, Alex W.

    AU - Mackey, David A.

    AU - Willoughby, Colin

    AU - Sherwin, Trevor

    AU - Crosier, Philip S.

    AU - McGhee, Charles N.

    AU - Vincent, Andrea L.

    PY - 2015/12/5

    Y1 - 2015/12/5

    N2 - PURPOSE:Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.DESIGN:Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.PARTICIPANTS:Four ERED families, including 28 affected and 17 unaffected individuals.METHODS:HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle-niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.MAIN OUTCOME MEASURES:Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.RESULTS:Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562-112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ-TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.CONCLUSIONS:The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.

    AB - PURPOSE:Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.DESIGN:Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.PARTICIPANTS:Four ERED families, including 28 affected and 17 unaffected individuals.METHODS:HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle-niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.MAIN OUTCOME MEASURES:Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.RESULTS:Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562-112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ-TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.CONCLUSIONS:The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.

    KW - corneal dystrophy

    KW - collagen XVII

    KW - epithelial recurrent erosion dystrophy (ERED)

    U2 - 10.1016/j.ophtha.2015.12.008

    DO - 10.1016/j.ophtha.2015.12.008

    M3 - Article

    VL - 123

    SP - 709

    EP - 722

    JO - Ophthalmology: Journal of the American Academy of Ophthalmology

    T2 - Ophthalmology: Journal of the American Academy of Ophthalmology

    JF - Ophthalmology: Journal of the American Academy of Ophthalmology

    SN - 0161-6420

    IS - 4

    ER -