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Thermodynamic stability and denaturation kinetics of a benign natural transthyretin mutant identified in a danish kindred

Academic Article
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Overview

authors

  • Groenning, M.
  • Campos, R. I.
  • Fagerberg, C.
  • Rasmussen, A. A.
  • Eriksen, U. H.
  • Powers, Evan
  • Hammarstrom, P.

publication date

  • June 2011

journal

  • Amyloid-Journal of Protein Folding Disorders  Journal

abstract

  • The disease phenotype of transthyretin (TTR) is dramatically influenced by single point mutations in the TTR gene. Herein, we report on a novel mutation D99N (Asp99Asn) in TTR found in a Danish kindred. None of the family members carrying this mutation have so far shown any clinical signs of amyloidosis. One carrier found compound heterozygous for TTR D99N and L111M (Leu111Met) associated with cardiac amyloid is asymptomatic (42 years). Disease severity can often be linked to both the kinetics of fibril formation and the degree of destabilisation of the native state. In this study, we show that the thermodynamic stability and rate of tetramer dissociation of the variant TTR D99N is unchanged or slightly more stable than wild type (WT) TTR. Furthermore, the in vitro fibrillation kinetics of the variant reveals an unchanged or slightly suppressed tendency to form fibrils compared to WT. Thus, the in vitro experiments support the lack of clinical symptoms observed so far for the TTR D99N carriers. In line with this, studies on kinetic stability and fibrillation kinetics reveal indistinguishable stability of TTR heterotetramers D99N/L111M compared to the heterotetramers WT/L111M. In conclusion, TTR D99N is predicted to be a non-pathogenic benign mutation with WT properties.

subject areas

  • Denmark
  • Female
  • Genetics, Population
  • Humans
  • Kinetics
  • Male
  • Models, Molecular
  • Pedigree
  • Point Mutation
  • Prealbumin
  • Protein Conformation
  • Protein Denaturation
  • Protein Folding
  • Thermodynamics
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Research

keywords

  • Amyloidosis
  • kinetics
  • mutation
  • stability
  • transthyretin
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Identity

International Standard Serial Number (ISSN)

  • 1350-6129

Digital Object Identifier (DOI)

  • 10.3109/13506129.2011.560215

PubMed ID

  • 21406045
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Additional Document Info

start page

  • 35

end page

  • 46

volume

  • 18

issue

  • 2

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