Mutation-Induced Deamidation of Corneal Dystrophy-Related Transforming Growth Factor β-Induced Protein

Nadia Sukusu Nielsen, Dennis Wilkens Juhl, Ebbe Toftgaard Poulsen, Marie V Lukassen, Emil Christian Poulsen, Michael W Risør, Carsten Scavenius, Jan Johannes Enghild

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Mutations in the transforming growth factor β-induced protein (TGFBIp) cause phenotypically diverse corneal dystrophies, where protein aggregation in the cornea leads to severe visual impairment. Previous studies have shown a relationship between mutant-specific corneal dystrophy phenotypes and the thermodynamic stability of TGFBIp. Using LC-MS/MS and NMR, we investigated correlations between the structural integrity of disease-related mutants of the fourth FAS1 domain (FAS1-4) and deamidation of TGFBIp residue Asn622. We observed a high rate of Asn622 deamidation in the A546D and A546D/P551Q FAS1-4 mutants that were both largely unstructured by NMR. Conversely, the more structurally organized A546T and V624M FAS1-4 mutants had reduced deamidation rates suggesting that a folded and stable FAS1-4 domain precludes Asn622 deamidation. Wild-type (WT), R555Q and R555W FAS1-4 mutants displayed very slow deamidation, which agrees with their similar and ordered NMR structures, where Asn622 is in a locked conformation. We confirmed the FAS1-4 mutational effect on deamidation rates in full-length TGFBIp mutants and found a similar ranking compared to the FAS1-4 domain alone. Consequently, the deamidation rate of Asn622 can be used to predict the structural effect of the many destabilizing/stabilizing mutations reported for TGFBIp. In addition, the deamidation of Asn622 may influence the pathophysiology of TGFBIp-induced corneal dystrophies.

Original languageEnglish
Pages (from-to)6470–6480
Number of pages11
Publication statusPublished - 28 Nov 2017


  • Journal Article


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