ArticleProceedings of the National Academy of Sciences of the United States of America2018
Unusual duplication mutation in a surface loop of human transthyretin leads to an aggressive drug-resistant amyloid disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 32 citations in OpenAlex.
- Transthyretin Amyloidosis Due to a Rare TTR Val142del Deletion With Relatively Early Clinical Manifestations.JACC. Case reports · 2026Article
- UniqueAnnals of laboratory medicine · 2026Article
- Virome and Experimental Analysis Reveal Tryptophan-Like Dissolved Organic Matter Contributes to the Persistence of Plant Viruses in River Water.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Clinical and Biochemical Characterization of Hereditary ATTR Amyloidosis Caused by a Novel Transthyretin Variant V121A (p.V141A).International journal of molecular sciences · 2025Article
- Identification of the interfacial regions in misfolded transthyretin oligomers.Biochimica et biophysica acta. Proteins and proteomics · 2024Article
- Degradation versus fibrillogenesis, two alternative pathways modulated by seeds and glycosaminoglycans.Protein science : a publication of the Protein Society · 2024Article
- A molecular basis for tetramer destabilization and aggregation of transthyretin Ala97Ser.Protein science : a publication of the Protein Society · 2023Article
- Toxic Misfolded Transthyretin Oligomers with Different Molecular Conformations Formed through Distinct Oligomerization Pathways.Biochemistry · 2022Article
- The genetics of cardiac amyloidosis.Heart failure reviews · 2022Review
- Current and Emerging Therapies for Hereditary Transthyretin Amyloidosis: Strides Towards a Brighter Future.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- In Vitro and In Vivo Effects of SerpinA1 on the Modulation of Transthyretin Proteolysis.International journal of molecular sciences · 2021Article
- Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism.International journal of molecular sciences · 2021Review
- Aggregation-Prone Structural Ensembles of Transthyretin Collected With Regression Analysis for NMR Chemical Shift.Frontiers in molecular biosciences · 2021Article
- Untangling Amyloidosis: Recent Advances in Cardiac Amyloidosis.International journal of heart failure · 2020Review
- Disruption of the CD Loop by Enzymatic Cleavage Promotes the Formation of Toxic Transthyretin Oligomers through a Common Transthyretin Misfolding Pathway.Biochemistry · 2020Article
- Amyloidosis in Heart Failure.Current heart failure reports · 2019Review
- A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH.The Journal of biological chemistry · 2019Article
- Plasminogen activation triggers transthyretin amyloidogenesisThe Journal of biological chemistry · 2018Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Transthyretin (TTR) is a globular tetrameric transport protein in plasma. Nearly 140 single amino acid substitutions in TTR cause life-threatening amyloid disease. We report a one-of-a-kind pathological variant featuring a Glu51, Ser52 duplication mutation (Glu51_Ser52dup). The proband, heterozygous for the mutation, exhibited an unusually aggressive amyloidosis that was refractory to treatment with the small-molecule drug diflunisal. To understand the poor treatment response and expand therapeutic options, we explored the structure and stability of recombinant Glu51_Ser52dup. The duplication did not alter the protein secondary or tertiary structure but decreased the stability of the TTR monomer and tetramer. Diflunisal, which bound with near-micromolar affinity, partially restored tetramer stability. The duplication had no significant effect on the free energy and enthalpy of diflunisal binding, and hence on the drug-protein interactions. However, the duplication induced tryptic digestion of TTR at near-physiological conditions, releasing a C-terminal fragment 49-129 that formed amyloid fibrils under conditions in which the full-length protein did not. Such C-terminal fragments, along with the full-length TTR, comprise amyloid deposits in vivo. Bioinformatics and structural analyses suggested that increased disorder in the surface loop, which contains the Glu51_Ser52dup duplication, not only helped generate amyloid-forming fragments but also decreased structural protection in the amyloidogenic residue segment 25-34, promoting misfolding of the full-length protein. Our studies of a unique duplication mutation explain its diflunisal-resistant nature, identify misfolding pathways for amyloidogenic TTR variants, and provide therapeutic targets to inhibit amyloid fibril formation by variant TTR.
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