A novel role for CRIM1 in the corneal response to UV and pterygium development

Eleanora Maurizi, Davide Schiroli, SD Atkinson, Laura Mairs, David Courtney, Barry O'Hagan, V. E. McGilligan, Alistair T Pagnamenta, Jenny C Taylor, Jesus J.D. Vasquez, Daniel E. Illanes-Velarde, Dave Goldsmith, Pieter Gouws, Jonathan Moore, M. Andrew Nesbit, Tara C. B. Moore

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Abstract

Pterygium is a pathological proliferative condition of the ocular surface, characterized by formation of a highly vascularized, fibrous tissue arising from the limbus that invades the central cornea leading to visual disturbance and, if untreated, blindness. Whilst chronic ultraviolet (UV) light exposure plays a major role in its pathogenesis, higher susceptibility to pterygium is observed in some families, suggesting a genetic component.In this study, a Northern Irish family affected by pterygium but reporting little direct exposure to UV was identified carrying a missense variant in CRIM1 NM_016441.2: c.1235 A>C (H412P) through whole-exome sequencing and subsequent analysis. CRIM1 is expressed in the developing eye, adult cornea and conjunctiva, having a role in cell differentiation and migration but also in angiogenesis, all processes involved in pterygium formation. We demonstrate elevated CRIM1 expression in pterygium tissue from additional individual Northern Irish patients compared to unaffected conjunctival controls. UV irradiation of HCE-S cells resulted in an increase in ERK phosphorylation and CRIM1 expression, the latter further elevated by the addition of the MEK1/2 inhibitor, U0126. Conversely, siRNA knockdown of CRIM1 led to decreased UV-induced ERK phosphorylation and increased BCL2 expression.Transient expression of the mutant H412P CRIM1 in corneal epithelial HCE-S cells showed that, unlike wild-type CRIM1, it was unable to reduce the cell proliferation, increased ERK phosphorylation and apoptosis induced through a decrease of BCL2 expression levels.We propose here a series of intracellular events where CRIM1 regulation of the ERK pathway prevents UV-induced cell proliferation and may play an important role in the in the pathogenesis of pterygium. Keywords: CRIM1; pterygium; UV; proliferation; ERK; apoptosis; variantAbbreviations: BCL2, B-cell lymphoma 2; BMP, Bone Morphogenetic Proteins; CRIM1, Cysteine Rich Motoneuron protein1; EMT, Epithelial mesenchymal transition; ERK (I), Extracellular signal–regulated kinases (Inhibitor); HCE-S, Human Corneal Epithelial cells; IC, Impression Cytology; IGV, Integrative Genomic Viewer; MAF, Minor allele frequency; MAPK, Mitogen-activated protein kinases; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NGS, Next Generation sequencing; NI, Northern Irish; PolyPhen, Polymorphism Phenotyping; SIFT, Sorting Intolerant From Tolerant; TiGER, Tissue-specific Gene Expression and Regulation; TGF-beta transforming Growth Factor- (Induced); TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labelling; VEGFA, Vascular Endothelial Growth FactorA; VW(F)-C, Von Willebrand (Factor) C; WES, Whole Exome Sequencing. 
LanguageEnglish
Article numberYEXER_2018_435_R1
JournalExperimental Eye Research
Early online date24 Oct 2018
DOIs
Publication statusE-pub ahead of print - 24 Oct 2018

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Pterygium
Exome
Phosphorylation
Cornea
Cell Proliferation
Apoptosis
Bone Morphogenetic Protein 2
Epithelial-Mesenchymal Transition
DNA Nucleotidylexotransferase
MAP Kinase Signaling System
Conjunctiva
Extracellular Signal-Regulated MAP Kinases
In Situ Nick-End Labeling
von Willebrand Factor
Gene Expression Regulation
Transforming Growth Factors
Motor Neurons
B-Cell Lymphoma
Blindness
Ultraviolet Rays

Keywords

  • pterygium
  • genetics
  • Cornea
  • Ultraviolet light
  • Mutation
  • Proliferation

Cite this

Maurizi, Eleanora ; Schiroli, Davide ; Atkinson, SD ; Mairs, Laura ; Courtney, David ; O'Hagan, Barry ; McGilligan, V. E. ; Pagnamenta, Alistair T ; Taylor, Jenny C ; Vasquez, Jesus J.D. ; Illanes-Velarde, Daniel E. ; Goldsmith, Dave ; Gouws, Pieter ; Moore, Jonathan ; Nesbit, M. Andrew ; Moore, Tara C. B. / A novel role for CRIM1 in the corneal response to UV and pterygium development. 2018.
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abstract = "Pterygium is a pathological proliferative condition of the ocular surface, characterized by formation of a highly vascularized, fibrous tissue arising from the limbus that invades the central cornea leading to visual disturbance and, if untreated, blindness. Whilst chronic ultraviolet (UV) light exposure plays a major role in its pathogenesis, higher susceptibility to pterygium is observed in some families, suggesting a genetic component.In this study, a Northern Irish family affected by pterygium but reporting little direct exposure to UV was identified carrying a missense variant in CRIM1 NM_016441.2: c.1235 A>C (H412P) through whole-exome sequencing and subsequent analysis. CRIM1 is expressed in the developing eye, adult cornea and conjunctiva, having a role in cell differentiation and migration but also in angiogenesis, all processes involved in pterygium formation. We demonstrate elevated CRIM1 expression in pterygium tissue from additional individual Northern Irish patients compared to unaffected conjunctival controls. UV irradiation of HCE-S cells resulted in an increase in ERK phosphorylation and CRIM1 expression, the latter further elevated by the addition of the MEK1/2 inhibitor, U0126. Conversely, siRNA knockdown of CRIM1 led to decreased UV-induced ERK phosphorylation and increased BCL2 expression.Transient expression of the mutant H412P CRIM1 in corneal epithelial HCE-S cells showed that, unlike wild-type CRIM1, it was unable to reduce the cell proliferation, increased ERK phosphorylation and apoptosis induced through a decrease of BCL2 expression levels.We propose here a series of intracellular events where CRIM1 regulation of the ERK pathway prevents UV-induced cell proliferation and may play an important role in the in the pathogenesis of pterygium. Keywords: CRIM1; pterygium; UV; proliferation; ERK; apoptosis; variantAbbreviations: BCL2, B-cell lymphoma 2; BMP, Bone Morphogenetic Proteins; CRIM1, Cysteine Rich Motoneuron protein1; EMT, Epithelial mesenchymal transition; ERK (I), Extracellular signal–regulated kinases (Inhibitor); HCE-S, Human Corneal Epithelial cells; IC, Impression Cytology; IGV, Integrative Genomic Viewer; MAF, Minor allele frequency; MAPK, Mitogen-activated protein kinases; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NGS, Next Generation sequencing; NI, Northern Irish; PolyPhen, Polymorphism Phenotyping; SIFT, Sorting Intolerant From Tolerant; TiGER, Tissue-specific Gene Expression and Regulation; TGF-beta transforming Growth Factor- (Induced); TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labelling; VEGFA, Vascular Endothelial Growth FactorA; VW(F)-C, Von Willebrand (Factor) C; WES, Whole Exome Sequencing. ",
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author = "Eleanora Maurizi and Davide Schiroli and SD Atkinson and Laura Mairs and David Courtney and Barry O'Hagan and McGilligan, {V. E.} and Pagnamenta, {Alistair T} and Taylor, {Jenny C} and Vasquez, {Jesus J.D.} and Illanes-Velarde, {Daniel E.} and Dave Goldsmith and Pieter Gouws and Jonathan Moore and Nesbit, {M. Andrew} and Moore, {Tara C. B.}",
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Maurizi, E, Schiroli, D, Atkinson, SD, Mairs, L, Courtney, D, O'Hagan, B, McGilligan, VE, Pagnamenta, AT, Taylor, JC, Vasquez, JJD, Illanes-Velarde, DE, Goldsmith, D, Gouws, P, Moore, J, Nesbit, MA & Moore, TCB 2018, 'A novel role for CRIM1 in the corneal response to UV and pterygium development'. https://doi.org/10.1016/j.exer.2018.10.012

A novel role for CRIM1 in the corneal response to UV and pterygium development. / Maurizi, Eleanora; Schiroli, Davide; Atkinson, SD; Mairs, Laura; Courtney, David; O'Hagan, Barry; McGilligan, V. E.; Pagnamenta, Alistair T; Taylor, Jenny C; Vasquez, Jesus J.D.; Illanes-Velarde, Daniel E.; Goldsmith, Dave; Gouws, Pieter; Moore, Jonathan; Nesbit, M. Andrew; Moore, Tara C. B.

24.10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel role for CRIM1 in the corneal response to UV and pterygium development

AU - Maurizi, Eleanora

AU - Schiroli, Davide

AU - Atkinson, SD

AU - Mairs, Laura

AU - Courtney, David

AU - O'Hagan, Barry

AU - McGilligan, V. E.

AU - Pagnamenta, Alistair T

AU - Taylor, Jenny C

AU - Vasquez, Jesus J.D.

AU - Illanes-Velarde, Daniel E.

AU - Goldsmith, Dave

AU - Gouws, Pieter

AU - Moore, Jonathan

AU - Nesbit, M. Andrew

AU - Moore, Tara C. B.

PY - 2018/10/24

Y1 - 2018/10/24

N2 - Pterygium is a pathological proliferative condition of the ocular surface, characterized by formation of a highly vascularized, fibrous tissue arising from the limbus that invades the central cornea leading to visual disturbance and, if untreated, blindness. Whilst chronic ultraviolet (UV) light exposure plays a major role in its pathogenesis, higher susceptibility to pterygium is observed in some families, suggesting a genetic component.In this study, a Northern Irish family affected by pterygium but reporting little direct exposure to UV was identified carrying a missense variant in CRIM1 NM_016441.2: c.1235 A>C (H412P) through whole-exome sequencing and subsequent analysis. CRIM1 is expressed in the developing eye, adult cornea and conjunctiva, having a role in cell differentiation and migration but also in angiogenesis, all processes involved in pterygium formation. We demonstrate elevated CRIM1 expression in pterygium tissue from additional individual Northern Irish patients compared to unaffected conjunctival controls. UV irradiation of HCE-S cells resulted in an increase in ERK phosphorylation and CRIM1 expression, the latter further elevated by the addition of the MEK1/2 inhibitor, U0126. Conversely, siRNA knockdown of CRIM1 led to decreased UV-induced ERK phosphorylation and increased BCL2 expression.Transient expression of the mutant H412P CRIM1 in corneal epithelial HCE-S cells showed that, unlike wild-type CRIM1, it was unable to reduce the cell proliferation, increased ERK phosphorylation and apoptosis induced through a decrease of BCL2 expression levels.We propose here a series of intracellular events where CRIM1 regulation of the ERK pathway prevents UV-induced cell proliferation and may play an important role in the in the pathogenesis of pterygium. Keywords: CRIM1; pterygium; UV; proliferation; ERK; apoptosis; variantAbbreviations: BCL2, B-cell lymphoma 2; BMP, Bone Morphogenetic Proteins; CRIM1, Cysteine Rich Motoneuron protein1; EMT, Epithelial mesenchymal transition; ERK (I), Extracellular signal–regulated kinases (Inhibitor); HCE-S, Human Corneal Epithelial cells; IC, Impression Cytology; IGV, Integrative Genomic Viewer; MAF, Minor allele frequency; MAPK, Mitogen-activated protein kinases; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NGS, Next Generation sequencing; NI, Northern Irish; PolyPhen, Polymorphism Phenotyping; SIFT, Sorting Intolerant From Tolerant; TiGER, Tissue-specific Gene Expression and Regulation; TGF-beta transforming Growth Factor- (Induced); TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labelling; VEGFA, Vascular Endothelial Growth FactorA; VW(F)-C, Von Willebrand (Factor) C; WES, Whole Exome Sequencing. 

AB - Pterygium is a pathological proliferative condition of the ocular surface, characterized by formation of a highly vascularized, fibrous tissue arising from the limbus that invades the central cornea leading to visual disturbance and, if untreated, blindness. Whilst chronic ultraviolet (UV) light exposure plays a major role in its pathogenesis, higher susceptibility to pterygium is observed in some families, suggesting a genetic component.In this study, a Northern Irish family affected by pterygium but reporting little direct exposure to UV was identified carrying a missense variant in CRIM1 NM_016441.2: c.1235 A>C (H412P) through whole-exome sequencing and subsequent analysis. CRIM1 is expressed in the developing eye, adult cornea and conjunctiva, having a role in cell differentiation and migration but also in angiogenesis, all processes involved in pterygium formation. We demonstrate elevated CRIM1 expression in pterygium tissue from additional individual Northern Irish patients compared to unaffected conjunctival controls. UV irradiation of HCE-S cells resulted in an increase in ERK phosphorylation and CRIM1 expression, the latter further elevated by the addition of the MEK1/2 inhibitor, U0126. Conversely, siRNA knockdown of CRIM1 led to decreased UV-induced ERK phosphorylation and increased BCL2 expression.Transient expression of the mutant H412P CRIM1 in corneal epithelial HCE-S cells showed that, unlike wild-type CRIM1, it was unable to reduce the cell proliferation, increased ERK phosphorylation and apoptosis induced through a decrease of BCL2 expression levels.We propose here a series of intracellular events where CRIM1 regulation of the ERK pathway prevents UV-induced cell proliferation and may play an important role in the in the pathogenesis of pterygium. Keywords: CRIM1; pterygium; UV; proliferation; ERK; apoptosis; variantAbbreviations: BCL2, B-cell lymphoma 2; BMP, Bone Morphogenetic Proteins; CRIM1, Cysteine Rich Motoneuron protein1; EMT, Epithelial mesenchymal transition; ERK (I), Extracellular signal–regulated kinases (Inhibitor); HCE-S, Human Corneal Epithelial cells; IC, Impression Cytology; IGV, Integrative Genomic Viewer; MAF, Minor allele frequency; MAPK, Mitogen-activated protein kinases; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NGS, Next Generation sequencing; NI, Northern Irish; PolyPhen, Polymorphism Phenotyping; SIFT, Sorting Intolerant From Tolerant; TiGER, Tissue-specific Gene Expression and Regulation; TGF-beta transforming Growth Factor- (Induced); TUNEL, Terminal deoxynucleotidyl transferase dUTP nick end labelling; VEGFA, Vascular Endothelial Growth FactorA; VW(F)-C, Von Willebrand (Factor) C; WES, Whole Exome Sequencing. 

KW - pterygium

KW - genetics

KW - Cornea

KW - Ultraviolet light

KW - Mutation

KW - Proliferation

U2 - 10.1016/j.exer.2018.10.012

DO - 10.1016/j.exer.2018.10.012

M3 - Article

M1 - YEXER_2018_435_R1

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