Protein Analysis of the TGFBI R124H Mouse Model Gives Insight Into Phenotype Development of Granular Corneal Dystrophy

Marie V. Lukassen; Ebbe Toftgaard Poulsen; Jack Donaghy; Emilie Hage Mogensen; Kathleen A. Christie; Hila Roshanravan; Larry DeDionisio; M. Andrew Nesbit; Tara C. B. Moore; Jan J Enghild

doi:10.1002/prca.201900072

Protein Analysis of the TGFBI R124H Mouse Model Gives Insight Into Phenotype Development of Granular Corneal Dystrophy

Marie V. Lukassen, Ebbe Toftgaard Poulsen, Jack Donaghy, Emilie Hage Mogensen, Kathleen A. Christie, Hila Roshanravan, Larry DeDionisio, M. Andrew Nesbit, Tara C. B. Moore, Jan J Enghild

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Abstract

Purpose: Mutations in the transforming growth factor β-induced protein (TGFBIp) are associated with TGFBI-linked corneal dystrophies, which manifests as protein deposits in the cornea. A total of 70 different disease-causing mutations have been reported so far including the common R124H substitution, which is associated with granular corneal dystrophy type 2 (GCD2). The disease mechanism of GCD2 is not known and the current treatments only offer temporary relief due to the reoccurrence of deposits.

Experimental design: The corneal protein profiles of the three genotypes (wild-type (WT), heterozygotes, and homozygotes) of a GCD2 mouse model are compared using label-free quantitative LC-MS/MS.

Results: The mice do not display corneal protein deposits and the global protein expression between the three genotypes is highly similar. However, the expression of mutated TGFBIp is 41% of that of the WT protein.

Conclusions and clinical relevance: It is proposed that the lowered expression level of mutant TGFBIp protein relative to WT protein is the direct cause of the missing development of corneal deposits in the mouse. The overall protein profiles of the corneas are not impacted by the reduced amount of TGFBIp. Altogether, this supports a partial reduction in mutated TGFBIp as a potential treatment strategy for GCD2.

Original language	English
Article number	1900072
Journal	PROTEOMICS - Clinical Applications
Volume	14
Issue number	6
Early online date	18 Jun 2020
DOIs	https://doi.org/10.1002/prca.201900072
Publication status	Published online - 18 Jun 2020

Bibliographical note

Funding Information:
The authors thank Dr. Shigeto Shimmura (Keio University School of Medicine) and Dr. Eung Kweon Kim (Yonsei University College of Medicine) for sharing of the TGFBI R124H mouse model. The project was supported by the VELUX Foundation (00014557), Danish Council for Independent Research—Medical Sciences (DFF‐4004‐00471), the Novo Nordisk Foundation (Bio‐MS), and Dagmar Marshalls Fond.

Publisher Copyright:
© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

2DE immunoblotting
cornea
granular corneal dystrophy type 2
label-free quantification
transforming growth factor β-induced protein

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lukassen et al_2020- accepted manuscriptAuthor Accepted Manuscript, 615 KB
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Cite this

Lukassen, M. V., Toftgaard Poulsen, E., Donaghy, J., Hage Mogensen, E., Christie, K. A., Roshanravan, H., DeDionisio, L., Nesbit, M. A., Moore, T. C. B., & Enghild, J. J. (2020). Protein Analysis of the TGFBI R124H Mouse Model Gives Insight Into Phenotype Development of Granular Corneal Dystrophy. PROTEOMICS - Clinical Applications, 14(6), Article 1900072. Advance online publication. https://doi.org/10.1002/prca.201900072

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title = "Protein Analysis of the TGFBI R124H Mouse Model Gives Insight Into Phenotype Development of Granular Corneal Dystrophy",

abstract = "Purpose: Mutations in the transforming growth factor β-induced protein (TGFBIp) are associated with TGFBI-linked corneal dystrophies, which manifests as protein deposits in the cornea. A total of 70 different disease-causing mutations have been reported so far including the common R124H substitution, which is associated with granular corneal dystrophy type 2 (GCD2). The disease mechanism of GCD2 is not known and the current treatments only offer temporary relief due to the reoccurrence of deposits.Experimental design: The corneal protein profiles of the three genotypes (wild-type (WT), heterozygotes, and homozygotes) of a GCD2 mouse model are compared using label-free quantitative LC-MS/MS.Results: The mice do not display corneal protein deposits and the global protein expression between the three genotypes is highly similar. However, the expression of mutated TGFBIp is 41% of that of the WT protein.Conclusions and clinical relevance: It is proposed that the lowered expression level of mutant TGFBIp protein relative to WT protein is the direct cause of the missing development of corneal deposits in the mouse. The overall protein profiles of the corneas are not impacted by the reduced amount of TGFBIp. Altogether, this supports a partial reduction in mutated TGFBIp as a potential treatment strategy for GCD2.",

keywords = "2DE immunoblotting, cornea, granular corneal dystrophy type 2, label-free quantification, transforming growth factor β-induced protein",

author = "Lukassen, {Marie V.} and {Toftgaard Poulsen}, Ebbe and Jack Donaghy and {Hage Mogensen}, Emilie and Christie, {Kathleen A.} and Hila Roshanravan and Larry DeDionisio and Nesbit, {M. Andrew} and Moore, {Tara C. B.} and Enghild, {Jan J}",

note = "Funding Information: The authors thank Dr. Shigeto Shimmura (Keio University School of Medicine) and Dr. Eung Kweon Kim (Yonsei University College of Medicine) for sharing of the TGFBI R124H mouse model. The project was supported by the VELUX Foundation (00014557), Danish Council for Independent Research—Medical Sciences (DFF‐4004‐00471), the Novo Nordisk Foundation (Bio‐MS), and Dagmar Marshalls Fond. Publisher Copyright: {\textcopyright} 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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Lukassen, MV, Toftgaard Poulsen, E, Donaghy, J, Hage Mogensen, E, Christie, KA, Roshanravan, H, DeDionisio, L, Nesbit, MA , Moore, TCB & Enghild, JJ 2020, 'Protein Analysis of the TGFBI R124H Mouse Model Gives Insight Into Phenotype Development of Granular Corneal Dystrophy', PROTEOMICS - Clinical Applications, vol. 14, no. 6, 1900072. https://doi.org/10.1002/prca.201900072

TY - JOUR

T1 - Protein Analysis of the TGFBI R124H Mouse Model Gives Insight Into Phenotype Development of Granular Corneal Dystrophy

AU - Lukassen, Marie V.

AU - Toftgaard Poulsen, Ebbe

AU - Donaghy, Jack

AU - Hage Mogensen, Emilie

AU - Christie, Kathleen A.

AU - Roshanravan, Hila

AU - DeDionisio, Larry

AU - Nesbit, M. Andrew

AU - Moore, Tara C. B.

AU - Enghild, Jan J

N1 - Funding Information: The authors thank Dr. Shigeto Shimmura (Keio University School of Medicine) and Dr. Eung Kweon Kim (Yonsei University College of Medicine) for sharing of the TGFBI R124H mouse model. The project was supported by the VELUX Foundation (00014557), Danish Council for Independent Research—Medical Sciences (DFF‐4004‐00471), the Novo Nordisk Foundation (Bio‐MS), and Dagmar Marshalls Fond. Publisher Copyright: © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/6/18

Y1 - 2020/6/18

N2 - Purpose: Mutations in the transforming growth factor β-induced protein (TGFBIp) are associated with TGFBI-linked corneal dystrophies, which manifests as protein deposits in the cornea. A total of 70 different disease-causing mutations have been reported so far including the common R124H substitution, which is associated with granular corneal dystrophy type 2 (GCD2). The disease mechanism of GCD2 is not known and the current treatments only offer temporary relief due to the reoccurrence of deposits.Experimental design: The corneal protein profiles of the three genotypes (wild-type (WT), heterozygotes, and homozygotes) of a GCD2 mouse model are compared using label-free quantitative LC-MS/MS.Results: The mice do not display corneal protein deposits and the global protein expression between the three genotypes is highly similar. However, the expression of mutated TGFBIp is 41% of that of the WT protein.Conclusions and clinical relevance: It is proposed that the lowered expression level of mutant TGFBIp protein relative to WT protein is the direct cause of the missing development of corneal deposits in the mouse. The overall protein profiles of the corneas are not impacted by the reduced amount of TGFBIp. Altogether, this supports a partial reduction in mutated TGFBIp as a potential treatment strategy for GCD2.

AB - Purpose: Mutations in the transforming growth factor β-induced protein (TGFBIp) are associated with TGFBI-linked corneal dystrophies, which manifests as protein deposits in the cornea. A total of 70 different disease-causing mutations have been reported so far including the common R124H substitution, which is associated with granular corneal dystrophy type 2 (GCD2). The disease mechanism of GCD2 is not known and the current treatments only offer temporary relief due to the reoccurrence of deposits.Experimental design: The corneal protein profiles of the three genotypes (wild-type (WT), heterozygotes, and homozygotes) of a GCD2 mouse model are compared using label-free quantitative LC-MS/MS.Results: The mice do not display corneal protein deposits and the global protein expression between the three genotypes is highly similar. However, the expression of mutated TGFBIp is 41% of that of the WT protein.Conclusions and clinical relevance: It is proposed that the lowered expression level of mutant TGFBIp protein relative to WT protein is the direct cause of the missing development of corneal deposits in the mouse. The overall protein profiles of the corneas are not impacted by the reduced amount of TGFBIp. Altogether, this supports a partial reduction in mutated TGFBIp as a potential treatment strategy for GCD2.

KW - 2DE immunoblotting

KW - cornea

KW - granular corneal dystrophy type 2

KW - label-free quantification

KW - transforming growth factor β-induced protein

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DO - 10.1002/prca.201900072

M3 - Article

C2 - 32558206

SN - 1862-8346

VL - 14

JO - PROTEOMICS - Clinical Applications

JF - PROTEOMICS - Clinical Applications

IS - 6

M1 - 1900072

ER -

Protein Analysis of the TGFBI R124H Mouse Model Gives Insight Into Phenotype Development of Granular Corneal Dystrophy

Abstract

Bibliographical note

Keywords

UN SDGs

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