Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy

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Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy. / Courtney, David G; Toftgaard Poulsen, Ebbe; Kennedy, Susan; Moore, Johnny E; Atkinson, Sarah D; Maurizi, Eleonora; Nesbit, M Andrew; Moore, C B Tara; Enghild, Jan J.

In: Investigative Ophthalmology & Visual Science, Vol. 56, No. 8, 01.07.2015, p. 4653-61.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Courtney, DG, Toftgaard Poulsen, E, Kennedy, S, Moore, JE, Atkinson, SD, Maurizi, E, Nesbit, MA, Moore, CBT & Enghild, JJ 2015, 'Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy', Investigative Ophthalmology & Visual Science, vol. 56, no. 8, pp. 4653-61. https://doi.org/10.1167/iovs.15-16922

APA

Courtney, D. G., Toftgaard Poulsen, E., Kennedy, S., Moore, J. E., Atkinson, S. D., Maurizi, E., Nesbit, M. A., Moore, C. B. T., & Enghild, J. J. (2015). Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy. Investigative Ophthalmology & Visual Science, 56(8), 4653-61. https://doi.org/10.1167/iovs.15-16922

CBE

Courtney DG, Toftgaard Poulsen E, Kennedy S, Moore JE, Atkinson SD, Maurizi E, Nesbit MA, Moore CBT, Enghild JJ. 2015. Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy. Investigative Ophthalmology & Visual Science. 56(8):4653-61. https://doi.org/10.1167/iovs.15-16922

MLA

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Author

Courtney, David G ; Toftgaard Poulsen, Ebbe ; Kennedy, Susan ; Moore, Johnny E ; Atkinson, Sarah D ; Maurizi, Eleonora ; Nesbit, M Andrew ; Moore, C B Tara ; Enghild, Jan J. / Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy. In: Investigative Ophthalmology & Visual Science. 2015 ; Vol. 56, No. 8. pp. 4653-61.

Bibtex

@article{78299649db024065a02ffbf60dbcf09a,
title = "Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy",
abstract = "PURPOSE: Transforming growth factor beta-induced (TGFBI)-related dystrophies constitute the most common heritable forms of corneal dystrophy worldwide. However, other than the underlying genotypes of these conditions, a limited knowledge exists of the exact pathomechanisms of these disorders. This study expands on our previous research investigating dystrophic stromal aggregates, with the aim of better elucidating the pathomechanism of two conditions arising from the most common TGFBI mutations: granular corneal dystrophy type 1 (GCD1; R555W) and lattice corneal dystrophy type 1 (LCD1; R124C).METHODS: Patient corneas with GCD1 and LCD1 were stained with hematoxylin and eosin and Congo red to visualize stromal nonamyloid and amyloid deposits, respectively. Laser capture microdissection was used to isolate aggregates and extracted protein was analyzed by mass spectrometry. Proteins were identified and their approximate abundances were determined. Spectra of TGFBIp peptides were also recorded and quantified.RESULTS: In total, three proteins were found within GCD1 aggregates that were absent in the healthy control corneal tissue. In comparison, an additional 18 and 24 proteins within stromal LCD1 and Bowman's LCD1 deposits, respectively, were identified. Variances surrounding the endogenous cleavage sites of TGFBIp were also noted. An increase in the number of residues experiencing cleavage was observed in both GCD1 aggregates and LCD1 deposits.CONCLUSIONS: The study reveals previously unknown differences between the protein composition of GCD1 and LCD1 aggregates, and confirms the presence of the HtrA1 protease in LCD1-amyloid aggregates. In addition, we find mutation-specific differences in the processing of mutant TGFBIp species, which may contribute to the variable phenotypes noted in TGFBI-related dystrophies.",
author = "Courtney, {David G} and {Toftgaard Poulsen}, Ebbe and Susan Kennedy and Moore, {Johnny E} and Atkinson, {Sarah D} and Eleonora Maurizi and Nesbit, {M Andrew} and Moore, {C B Tara} and Enghild, {Jan J}",
year = "2015",
month = jul,
day = "1",
doi = "10.1167/iovs.15-16922",
language = "English",
volume = "56",
pages = "4653--61",
journal = "Investigative Ophthalmology & Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology",
number = "8",

}

RIS

TY - JOUR

T1 - Protein Composition of TGFBI-R124C- and TGFBI-R555W- Associated Aggregates Suggests Multiple Mechanisms Leading to Lattice and Granular Corneal Dystrophy

AU - Courtney, David G

AU - Toftgaard Poulsen, Ebbe

AU - Kennedy, Susan

AU - Moore, Johnny E

AU - Atkinson, Sarah D

AU - Maurizi, Eleonora

AU - Nesbit, M Andrew

AU - Moore, C B Tara

AU - Enghild, Jan J

PY - 2015/7/1

Y1 - 2015/7/1

N2 - PURPOSE: Transforming growth factor beta-induced (TGFBI)-related dystrophies constitute the most common heritable forms of corneal dystrophy worldwide. However, other than the underlying genotypes of these conditions, a limited knowledge exists of the exact pathomechanisms of these disorders. This study expands on our previous research investigating dystrophic stromal aggregates, with the aim of better elucidating the pathomechanism of two conditions arising from the most common TGFBI mutations: granular corneal dystrophy type 1 (GCD1; R555W) and lattice corneal dystrophy type 1 (LCD1; R124C).METHODS: Patient corneas with GCD1 and LCD1 were stained with hematoxylin and eosin and Congo red to visualize stromal nonamyloid and amyloid deposits, respectively. Laser capture microdissection was used to isolate aggregates and extracted protein was analyzed by mass spectrometry. Proteins were identified and their approximate abundances were determined. Spectra of TGFBIp peptides were also recorded and quantified.RESULTS: In total, three proteins were found within GCD1 aggregates that were absent in the healthy control corneal tissue. In comparison, an additional 18 and 24 proteins within stromal LCD1 and Bowman's LCD1 deposits, respectively, were identified. Variances surrounding the endogenous cleavage sites of TGFBIp were also noted. An increase in the number of residues experiencing cleavage was observed in both GCD1 aggregates and LCD1 deposits.CONCLUSIONS: The study reveals previously unknown differences between the protein composition of GCD1 and LCD1 aggregates, and confirms the presence of the HtrA1 protease in LCD1-amyloid aggregates. In addition, we find mutation-specific differences in the processing of mutant TGFBIp species, which may contribute to the variable phenotypes noted in TGFBI-related dystrophies.

AB - PURPOSE: Transforming growth factor beta-induced (TGFBI)-related dystrophies constitute the most common heritable forms of corneal dystrophy worldwide. However, other than the underlying genotypes of these conditions, a limited knowledge exists of the exact pathomechanisms of these disorders. This study expands on our previous research investigating dystrophic stromal aggregates, with the aim of better elucidating the pathomechanism of two conditions arising from the most common TGFBI mutations: granular corneal dystrophy type 1 (GCD1; R555W) and lattice corneal dystrophy type 1 (LCD1; R124C).METHODS: Patient corneas with GCD1 and LCD1 were stained with hematoxylin and eosin and Congo red to visualize stromal nonamyloid and amyloid deposits, respectively. Laser capture microdissection was used to isolate aggregates and extracted protein was analyzed by mass spectrometry. Proteins were identified and their approximate abundances were determined. Spectra of TGFBIp peptides were also recorded and quantified.RESULTS: In total, three proteins were found within GCD1 aggregates that were absent in the healthy control corneal tissue. In comparison, an additional 18 and 24 proteins within stromal LCD1 and Bowman's LCD1 deposits, respectively, were identified. Variances surrounding the endogenous cleavage sites of TGFBIp were also noted. An increase in the number of residues experiencing cleavage was observed in both GCD1 aggregates and LCD1 deposits.CONCLUSIONS: The study reveals previously unknown differences between the protein composition of GCD1 and LCD1 aggregates, and confirms the presence of the HtrA1 protease in LCD1-amyloid aggregates. In addition, we find mutation-specific differences in the processing of mutant TGFBIp species, which may contribute to the variable phenotypes noted in TGFBI-related dystrophies.

U2 - 10.1167/iovs.15-16922

DO - 10.1167/iovs.15-16922

M3 - Journal article

C2 - 26207300

VL - 56

SP - 4653

EP - 4661

JO - Investigative Ophthalmology & Visual Science

JF - Investigative Ophthalmology & Visual Science

SN - 0146-0404

IS - 8

ER -