**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Maria del Carmen Fernandez-Ramirez

**Main Body of the Abstract**
ATTR amyloidosis is a degenerative disorder with diverse clinical manifestations, characterized by the pathologic deposition of the protein transthyretin. These amyloid aggregates of transthyretin (ATTR) can deposit in different parts of the body causing a diverse range of clinical phenotypes. Our lab aims to investigate a potential relationship between the different genotypes in ATTR patients and the structure of the ATTR fibrils formed, and whether the structure is influenced by the organ of deposition. Using cryo-electron microscopy, we have recently described how the mutation ATTRv-I84S can drive structural polymorphism in ex vivofibrils. Here we question whether the mutation ATTRv-T60A, which is the most common genetic ATTR variant in Ireland and UK, has a similar effect. To address these questions, we extracted and determined the structure of ATTR-T60A fibrils from multiple organs (heart, kidney, liver, and thyroid) from the same patient and from the heart of two additional patients. We have found an extreme homogeneity among all the structures, acquiring the “closed-gate morphology” found previously in ATTRwt and others ATTRv related to cardiac manifestations. This morphology is composed by two segments of the protein that interact together forming a polar channel, where the residues glycine 57 to isoleucine 68 “closes” this cavity. Our study suggests that ATTR-T60A fibrils adopt the same structural conformation in all patients, regardless of the organ of deposition. This conformation is similar to the one found in ATTRwt and most ATTR variants, indicating that the T60A mutation does not drive fibril polymorphism.



**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Maria del Carmen Fernandez-Ramirez

**Main Body of the Abstract**
ATTR amyloidosis is a degenerative disorder with diverse clinical manifestations, characterized by the pathologic deposition of the protein transthyretin. These amyloid aggregates of transthyretin (ATTR) can deposit in different parts of the body causing a diverse range of clinical phenotypes. Our lab aims to investigate a potential relationship between the different genotypes in ATTR patients and the structure of the ATTR fibrils formed, and whether the structure is influenced by the organ of deposition. Using cryo-electron microscopy, we have recently described how the mutation ATTRv-I84S can drive structural polymorphism in _ex vivo_fibrils. Here we question whether the mutation ATTRv-T60A, which is the most common genetic ATTR variant in Ireland and UK, has a similar effect. To address these questions, we extracted and determined the structure of ATTR-T60A fibrils from multiple organs (heart, kidney, liver, and thyroid) from the same patient and from the heart of two additional patients. We have found an extreme homogeneity among all the structures, acquiring the “closed-gate morphology” found previously in ATTRwt and others ATTRv related to cardiac manifestations. This morphology is composed by two segments of the protein that interact together forming a polar channel, where the residues glycine 57 to isoleucine 68 “closes” this cavity. Our study suggests that ATTR-T60A fibrils adopt the same structural conformation in all patients, regardless of the organ of deposition. This conformation is similar to the one found in ATTRwt and most ATTR variants, indicating that the T60A mutation does not drive fibril polymorphism.



Structural homogeneity of ex-vivo ATTR-T60A fibrils revealed by Cryo-EM PB6 (#134)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.