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Transthyretin mutagenesis: impact on amyloidogenesis and disease

2024Journal article Open access
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dc.contributor.authorAlmeida, Zaida L.
dc.contributor.authorVaz, Daniela C.
dc.contributor.authorBrito, Rui M. M.
dc.date.accessioned2024-06-11T14:55:57Z
dc.date.available2024-06-11T14:55:57Z
dc.date.issued2024
dc.descriptionFunding 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.).pt_PT
dc.description.abstractTransthyretin (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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationZaida 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: 10.1080/10408363.2024.2350379pt_PT
dc.identifier.doihttps://doi.org/10.1080/10408363.2024.2350379pt_PT
dc.identifier.eissn1549-781X
dc.identifier.urihttp://hdl.handle.net/10400.8/9708
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherTaylor & Francispt_PT
dc.relationCoimbra Chemistry Center
dc.relationCoimbra Chemistry Center
dc.relation.publisherversionhttps://www.tandfonline.com/doi/full/10.1080/10408363.2024.2350379pt_PT
dc.subjectAmyloidpt_PT
dc.subjectATTRpt_PT
dc.subjectAggregationpt_PT
dc.subjectTransthyretin (TTR)pt_PT
dc.subjectTTR variantspt_PT
dc.titleTransthyretin mutagenesis: impact on amyloidogenesis and diseasept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCoimbra Chemistry Center
oaire.awardTitleCoimbra Chemistry Center
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F00313%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F00313%2F2020/PT
oaire.citation.endPage25pt_PT
oaire.citation.startPage1pt_PT
oaire.citation.titleCritical Reviews in Clinical Laboratory Sciencespt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameBarroso de Moura Cipreste Vaz
person.givenNameDaniela
person.identifier.ciencia-id801A-7761-328C
person.identifier.orcid0000-0001-7562-4676
person.identifier.ridR-5243-2017
person.identifier.scopus-author-id6602838931
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscovery518f12af-3297-4334-b00b-c06e17b2cf27
relation.isProjectOfPublicationb9b006e0-f6d7-4144-9c0d-444e3d0d601c
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