Amyloid fibril polymorphism in the heart and liver of a patient with polyneuropathic ATTRv-V122Δ amyloidosis
Year: 2026
Type: article
Abstract: ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may result from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as cardiomyopathy, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from multisystem organ involvement. Over 220 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in explaining differential disease manifestations remains unclear. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart and the liver of an ATTRv patient carrying the V122∆ mutation, which is predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes. Cryo-EM analysis of fibrils from heart and liver of an ATTR amyloidosis patient with the V122Δ mutation reveals polymorphic single and double filaments, suggesting that fibril structural polymorphism may contribute to phenotypic variation in ATTR amyloidosis.
Source: Communications Biology
Authors: Yasmin Ahmed, Binh An Nguyen, Candace Kelly, Shumaila Afrin, Virender Singh, Bret M. Evers, John M. Shelton, Christian Lopez Escobar, Preeti Singh, Rose Pedretti, Lanie Wang, Parker Bassett, Maria del Carmen Fernandez-Ramirez, Maja Pekala, Andrew Lemoff, Barbara Kluve-Beckerman, Lorena Saelices
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
Funders: U.S. Department of Energy, Welch Foundation, American Heart Association, University of Texas Southwestern Medical Center, National Institutes of Health, Office of Science, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, Biological and Environmental Research, SLAC National Accelerator Laboratory, Common Fund
Awards: G1229526393, G2146062276, Study of the phenotypic variability of cardiac amyloidosis to develop peptide-based diagnostic tools, G2371548206, G262532246, G315621713, G3534087081, G4235786860, G4582736256, TEM for UT Southwestern Electron Microscopy Core Facility, G495301720, G498139845, G5001072352, G5570207115, SEM for UT Southwestern EM Core Facility, G6035979156, G6256846791, G7178301082, G7355090052, G751038967, G8255659214, G8382000481, NCCAT: National Center for CryoEM Access and Training, G8925327636, G9000060489, G969889393
OpenAlex ID: W7147352899