Cryo-EM structures of biopsy-derived TTR fibrils in hereditary transthyretin amyloidosis
Abstract Hereditary transthyretin amyloidosis (ATTRv) is a fatal autosomal dominant disease characterized by systemic deposition of transthyretin (TTR) amyloid fibrils, leading to progressive neuropathy and cardiomyopathy. More than 130 pathogenic mutations in the TTR gene have been identified, but their roles in TTR fibril formation and disease pathogenesis remain unclear. Here, using cryo-electron microscopy (cryo-EM), we present nineteen high-resolution TTR fibril structures (1.9-3.4 Å) from gastrocnemius muscle biopsies and vitreous humor of ten living ATTRv patients carrying nine distinct heterozygous mutations. Deep-learning-based analysis of cryo-EM densities enables semi-quantitative assessment of mutant or wild-type dominance within fibrils. These compositional profiles, combined with their structures, suggest an association between disease onset and the TTR species (wild-type or mutant) that primarily initiates amyloid formation. This biopsy-based workflow broadens access to patient tissue for amyloid structural studies, enabling systematic investigation of heterogeneous hereditary amyloidoses and the role of mutations in amyloid formation.
Authors
- Jiawei Liang (ORCID: https://orcid.org/0000-0003-0748-3183)
- Xujun Chu (ORCID: https://orcid.org/0000-0002-6497-1979)
- Wei Chi (ORCID: https://orcid.org/0000-0002-7424-3879)
- Conghui Ma
- Yue‐De Yang (ORCID: https://orcid.org/0000-0003-1579-7561)
- B Q Liu
- Jianwen Deng (ORCID: https://orcid.org/0000-0003-1206-1778)
- Guowei Yin (ORCID: https://orcid.org/0000-0003-2669-7160)
- Shaochong Zhang (ORCID: https://orcid.org/0000-0002-2212-7139)
- Wenjuan Wang (ORCID: https://orcid.org/0000-0001-9180-2823)
- Yixiao Liu (ORCID: https://orcid.org/0000-0002-2964-0007)
- Jionglin Bao
- Yu-Xin Zheng (ORCID: https://orcid.org/0009-0005-1542-3422)
- Lingchao Meng
- Zhenyu Li
Institutions
- Sun Yat-sen University (CN)
- Peking University (CN)
- The Seventh Affiliated Hospital of Sun Yat-sen University (CN)
- First Affiliated Hospital of Guangdong Pharmaceutical University (CN)
- Peking University First Hospital (CN)
- Southern Medical University Shenzhen Hospital (CN)
- He Eye Hospital (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-24
- DOI
- https://doi.org/10.1038/s41467-026-75850-8
- Primary Topic
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Chinese Academy of Medical Sciences
- Guangdong Science and Technology Department
- Peking University
- Science and Technology Department of Zhejiang Province