**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.**
Diana Canetti
Centre for Amyloidosis, University College London, London, UK

**Main Body of the Abstract**
Proteomics is routinely employed for amyloid typing and allows the identification of protein variants, which is diagnostically important in hereditary amyloidosis such as transthyretin (ATTR) amyloidosis. During a review of the proteomics data from ATTR patients attending the UK-National Amyloidosis Centre, we observed an unusually high number of tissue biopsies where the rare pathogenic H90D TTR variant was detected. The identification of this rare pathogenic variant in a large cohort of ATTR patients raised questions as to its source. The variant was not detected in fresh fat aspirates, or in the blood, except in one patient carrying H90D TTR mutation confirmed by genetics, or in tissues from an ATTR amyloid mouse model. The variant could be caused by non-enzymic oxidation of histidine in position 90 as the H->D transformation was also observed at other sites. Results from in vitro oxidation experiments using recombinant wild-type TTR and ex vivo ATTR fibrils suggest that the 90D variant can be generated artefactually from wild-type 90H TTR via radical-mediated oxidation of histidine, followed by its subsequent conversion to aspartic acid. This conversion probably occurs during storage. The identification of the H90D TTR variant in stored tissues by proteomics should be treated with caution in the absence of genetic information.



**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.**
Diana Canetti
Centre for Amyloidosis, University College London, London, UK

**Main Body of the Abstract**
Proteomics is routinely employed for amyloid typing and allows the identification of protein variants, which is diagnostically important in hereditary amyloidosis such as transthyretin (ATTR) amyloidosis. During a review of the proteomics data from ATTR patients attending the UK-National Amyloidosis Centre, we observed an unusually high number of tissue biopsies where the rare pathogenic H90D TTR variant was detected. The identification of this rare pathogenic variant in a large cohort of ATTR patients raised questions as to its source. The variant was not detected in fresh fat aspirates, or in the blood, except in one patient carrying H90D TTR mutation confirmed by genetics, or in tissues from an ATTR amyloid mouse model. The variant could be caused by non-enzymic oxidation of histidine in position 90 as the H->D transformation was also observed at other sites. Results from _in vitro_ oxidation experiments using recombinant wild-type TTR and _ex vivo_ ATTR fibrils suggest that the 90D variant can be generated artefactually from wild-type 90H TTR via radical-mediated oxidation of histidine, followed by its subsequent conversion to aspartic acid. This conversion probably occurs during storage. The identification of the H90D TTR variant in stored tissues by proteomics should be treated with caution in the absence of genetic information.



Oxidative conversion of transthyretin in formalin-fixed clinical amyloid samples results in the formation of the His90Asp variant. PB44 (#480)

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.