Corneal dystrophy mutations drive pathogenesis by targeting TGFBIp stability and solubility in a latent amyloid-forming domain

Marcel Stenvang, Nicholas P Schafer, Kirsten Gade Malmos, Adriana-Michelle Wolf Pérez, Olatz Niembro, Pietro Sormanni, Rajiv Vaid Basaiawmoit, Gunna Christiansen, Maria Andreasen, Daniel E Otzen

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

Abstract

Numerous mutations in the corneal protein TGFBIp lead to opaque extracellular deposits and corneal dystrophies (CDs). Here we elucidate the molecular origins underlying TGFBIp's mutation-induced increase in aggregation propensity through comprehensive biophysical and bioinformatic analyses of mutations associated with every major subtype of TGFBIp-linked CDs including lattice corneal dystrophy (LCD) and three subtypes of granular corneal dystrophy (GCD 1-3). LCD mutations at buried positions in the C-terminal Fas1-4 domain lead to decreased stability. GCD variants show biophysical profiles distinct from those of LCD mutations. GCD 1 and 3 mutations reduce solubility rather than stability. Half of the 50 positions within Fas1-4 most sensitive to mutation are associated with at least one known disease-causing mutation, including 10 of the top 11 positions. Thus, TGFBIp aggregation is driven by mutations that despite their physico-chemical diversity target either the stability or solubility of Fas1-4 in predictable ways, suggesting straightforward general therapeutic strategies.

Original languageEnglish
JournalJournal of Molecular Biology
Volume430
Issue8
Pages (from-to)1116-1140
Number of pages25
ISSN0022-2836
DOIs
Publication statusPublished - 13 Apr 2018

Keywords

  • TGFBIp
  • corneal dystrophy
  • disease-causing mutations
  • molecular pathology
  • protein aggregation

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