Comparison of two phenotypically distinct lattice corneal dystrophies caused by mutations in the transforming growth factor beta induced (TGFBI) gene.


Journal Article

PURPOSE: In this study, we investigated whether the phenotypic difference observed between two lattice corneal dystrophy type 1 (LCD type 1) cases caused by either a single A546D substitution or an A546D/P551Q double substitution in TGFBIp (transforming growth factor beta induced protein) can be ascribed to (i) a difference in the proteomes of corneal amyloid deposits, (ii) altered proteolysis of TGFBIp, or (iii) structural changes of TGFBIp introduced by the P551Q amino acid substitution. EXPERIMENTAL DESIGN: Amyloid deposits were isolated from the corneas of two siblings with LCD type 1 resulting from A546D/P551Q mutations in the TGFBI gene using laser capture microdissection and subsequently analyzed by LC-MS/MS. Proteolytic processing of TGFBIp was addressed by counting peptide spectra. Lastly, to study the possible effect of the P551Q substitution, recombinant FAS1-4 domain variants were subjected to in vitro stability assays. RESULTS: The amyloid proteomes and TGFBIp processing of the two A546D/P551Q LCD type 1 cases were similar to each other as well as to the A546D amyloid proteome previously reported by us. The stability assays revealed a minor destabilization of the FAS1-4 domain upon the addition of the P551Q mutation, moreover, it resulted in different accessibility to tryptic cleavage sites between the A546D and A546D/P551Q mutant FAS1-4 domain variants. CONCLUSION AND CLINICAL RELEVANCE: The difference in A546D and A546D/P551Q LCD type 1 phenotypes cannot be ascribed to altered corneal amyloid composition or altered in vivo proteolytic processing of TGFBIp. Instead, a small difference in thermodynamic stability introduced by the P551Q mutation most likely causes structural changes of TGFBIp. The MS proteomics data have been deposited to the ProteomeXchange with identifier PXD000307 (

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Cited Authors

  • Poulsen, ET; Runager, K; Risør, MW; Dyrlund, TF; Scavenius, C; Karring, H; Praetorius, J; Vorum, H; Otzen, DE; Klintworth, GK; Enghild, JJ

Published Date

  • April 2014

Published In

Volume / Issue

  • 8 / 3-4

Start / End Page

  • 168 - 177

PubMed ID

  • 24302499

Pubmed Central ID

  • 24302499

Electronic International Standard Serial Number (EISSN)

  • 1862-8354

Digital Object Identifier (DOI)

  • 10.1002/prca.201300058


  • eng

Conference Location

  • Germany