Hereditary ATTR Amyloidosis

Structure of ATTRv-F64S fibrils isolated from skin tissue of a living patient

Amyloid transthyretin-derived (ATTR) amyloidosis is a degenerative, systemic disease characterized by transthyretin fibril deposition in organs like the heart, kidneys, liver, and skin. ATTR amyloidosis causes peripheral polyneuropathy, cardiomyopathy and dysfunction of organs, often leading to fatal outcomes for patients if untreated.

            In the present study, we extracted pathogenic ATTR amyloid fibrils from the skin of a living patient carrying a rare genetic transthyretinmutation (F64S), and characterised the fibrils using immuno-histochemistry, mass spectrometry and cryo-EM. Using Mass Spectrometry, we show that the mutant form of transthyretin (TTR) is more likely to be incorporated into the amyloid fibrils, and we identify novel post-translational modifications of ATTR fibrils. Importantly, our work demonstrates that a minimal amount of skin tissue (less than ten milligrams) enables the determination of a high-resolution structure (2.8 Å), which shows structural conservation across different tissues and ATTR variants. To the best of our knowledge, this is the first amyloid fibril structure that has been determined from a living patient, and we anticipate that this work will guide the development of strain-specific therapeutic strategies for ATTR amyloidosis, paving the way towards personalised care.

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Structure of ATTRv-F64S amyloid fibrils derived from skin biopsy.
Yu J*, Zhang X*, Pinton S, Vacchi E, Cavalli A, Pecoraro M, Melli G and Boland A. bioRxiv, 2025.

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We thank all patients for their support of our reseaech.