Transthyretin mutagenesis: impact on amyloidogenesis and disease.

Crit Rev Clin Lab Sci

Chemistry Department and Coimbra Chemistry Centre - Institute of Molecular Sciences (CQC-IMS), University of Coimbra, Coimbra, Portugal.

Published: June 2024

AI Article Synopsis

  • * There are around 220 known single-point mutations in TTR, with 93% of these mutations deemed pathogenic, primarily affecting regions of the protein associated with the formation of amyloid fibrils.
  • * The review explores TTR's role in disease, including mutation effects, aggregation models, and current research protocols used for understanding and developing treatments for TTR-related amyloid diseases.

Article Abstract

Transthyretin (TTR), a homotetrameric protein found in plasma, cerebrospinal fluid, and the eye, plays a pivotal role in the onset of several amyloid diseases with high morbidity and mortality. Protein aggregation and fibril formation by wild-type TTR and its natural more amyloidogenic variants are hallmarks of ATTRwt and ATTRv amyloidosis, respectively. The formation of soluble amyloid aggregates and the accumulation of insoluble amyloid fibrils and deposits in multiple tissues can lead to organ dysfunction and cell death. The most frequent manifestations of ATTR are polyneuropathies and cardiomyopathies. However, clinical manifestations such as carpal tunnel syndrome, leptomeningeal, and ocular amyloidosis, among several others may also occur. This review provides an up-to-date listing of all single amino-acid mutations in TTR known to date. Of approximately 220 single-point mutations, 93% are considered pathogenic. Aspartic acid is the residue mutated with the highest frequency, whereas tryptophan is highly conserved. "Hot spot" mutation regions are mainly assigned to β-strands B, C, and D. This manuscript also reviews the protein aggregation models that have been proposed for TTR amyloid fibril formation and the transient conformational states that convert native TTR into aggregation-prone molecular species. Finally, it compiles the various TTR aggregation protocols currently in use for research and drug development purposes. In short, this article reviews and discusses TTR mutagenesis and amyloidogenesis, and their implications in disease onset.

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Source
http://dx.doi.org/10.1080/10408363.2024.2350379DOI Listing

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