Enhanced transthyretin tetramer stability following expression of an amyloid disease transsuppressor variant in mammalian cells

Academic Article


  • Background: The transthyretin (TTR) amyloidosis is an incurable fatal inherited disease that is characterized by progressive peripheral and autonomic neuropathy. It is caused by missense amyloidogenic mutations in the TTR gene that destabilize the native tetrameric state and lead to the cytotoxic misfolded monomeric state. One interesting variant (T119M) stabilizes heterotetramers with amyloidogenic TTR and, in the reported heterozygous individuals, protects the carriers from disease. In the present study, we characterize in vitro and in vivo the ectopic expression of the human T119M mutant, termed a transsuppressor for TTR amyloid disease. Methods: Lentiviral vectors encoding wild or mutant forms of human TTR were constructed and transduced to the human hepatocellular carcinoma cell line, HepG2, or mice. Heterooligomerization between T119M TTR and amyloidogenic variants was analysed by immunoprecipitation following western blotting. Results: T119M TTR was stably expressed in transduced HepG2 cells and was secreted as an oligomer that can interact with its native partner, retinol-binding protein. Importantly, the T119M TTR formed secreted heterooligomers with amyloidogenic TTR variants, V30M, L55P and V122I, in HepG2 cells that were more stable than the homooligomers of the same amyloidogenic TTR variants. Human T119M TTR also formed heterooligomers with V30M TTR in transduced mice. Conclusions: The results obtained in the present study demonstrate the stabilization of heterotetramers by T119M TTR in human cells and suggest that gene transfer of T119M TTR may have potential as a gene therapy for TTR amyloidosis. Copyright © 2008 John Wiley & Sons, Ltd.
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    Author List

  • Kamata M; Susanto MT; Chen ISY
  • Start Page

  • 103
  • End Page

  • 111
  • Volume

  • 11
  • Issue

  • 2