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Transthyretin mutagenesis: impact on amyloidogenesis and disease
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Advisor(s)
Abstract(s)
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 in vitro 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.
Description
Funding
This work was supported by COMPETE and CENTRO-202010. 13039/501100011929 and by Fundação para a Ciência e a Tecnologia (FCT) through grants UIDB/00313/2020 and UIDP/00313/2020 (to Coimbra Chemistry Center, University of Coimbra) and doctoral fellowship SFRH/BD/137991/2018 (to Z.L.A.).
Keywords
Amyloid ATTR Aggregation Transthyretin (TTR) TTR variants
Citation
Zaida L. Almeida, Daniela C. Vaz & Rui M. M. Brito (07 Jun 2024): Transthyretin mutagenesis: impact on amyloidogenesis and disease, Critical Reviews in Clinical Laboratory Sciences, DOI: 10.1080/10408363.2024.2350379
Publisher
Taylor & Francis