**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.**
Yasmin Ahmed, UT Southwestern Medical Center, Dallas, TX

**Main Body of the Abstract**
ATTR amyloidosis is a clinically diverse disease characterized by the pathological deposition of the protein transthyretin (TTR) in the form of amyloid fibrils into various organs. ATTR amyloidosis may be invoked by mutations in variant ATTR (ATTRv) amyloidosis, or aging in wild-type ATTR (ATTRwt) amyloidosis. ATTRwt generally presents as a cardiomyopathy phenotype, whereas ATTRv may manifest as polyneuropathy, cardiomyopathy, mixed, as well as many other symptoms stemming from secondary organ involvement. Over 130 different mutational variants of transthyretin have been identified, with many being associated with specific disease symptoms.1 The role of these mutations in the organotropism of fibril deposition and differential disease manifestation remains unclear. In the present work, we used cryo-electron microscopy to elucidate the molecular basis of two different mutations, V122I and V122Δ, which predominantly present as cardiomyopathy and polyneuropathy, respectively. Of note, V122I is the most common mutation worldwide, with 4% of African Americans carrying this allele in the US.2 We extracted fibrils from the hearts of two ATTR amyloidosis patients carrying either the V122I or V122Δ mutation, and determined their structures using cryo-electron microscopy. Our results provide insight on the structural differences between both mutations, as well as structural polymorphism in V122Δ amyloid fibrils. Further studies are needed to understand the structural differences may contribute to the phenotypic variation in ATTRv amyloidosis.



**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.**
Yasmin Ahmed, UT Southwestern Medical Center, Dallas, TX

**Main Body of the Abstract**
ATTR amyloidosis is a clinically diverse disease characterized by the pathological deposition of the protein transthyretin (TTR) in the form of amyloid fibrils into various organs. ATTR amyloidosis may be invoked by mutations in variant ATTR (ATTRv) amyloidosis, or aging in wild-type ATTR (ATTRwt) amyloidosis. ATTRwt generally presents as a cardiomyopathy phenotype, whereas ATTRv may manifest as polyneuropathy, cardiomyopathy, mixed, as well as many other symptoms stemming from secondary organ involvement. Over 130 different mutational variants of transthyretin have been identified, with many being associated with specific disease symptoms.^1^ The role of these mutations in the organotropism of fibril deposition and differential disease manifestation remains unclear. In the present work, we used cryo-electron microscopy to elucidate the molecular basis of two different mutations, V122I and V122Δ, which predominantly present as cardiomyopathy and polyneuropathy, respectively. Of note, V122I is the most common mutation worldwide, with 4% of African Americans carrying this allele in the US.^2^ We extracted fibrils from the hearts of two ATTR amyloidosis patients carrying either the V122I or V122Δ mutation, and determined their structures using cryo-electron microscopy. Our results provide insight on the structural differences between both mutations, as well as structural polymorphism in V122Δ amyloid fibrils. Further studies are needed to understand the structural differences may contribute to the phenotypic variation in ATTRv amyloidosis.



Structural Variations in ATTR Amyloidosis: Cryo-Electron Microscopy Examination of V122I and V122Δ Mutations PB7 (#150)

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.