{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T01:24:33Z","timestamp":1774315473231,"version":"3.50.1"},"reference-count":30,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006400","name":"Alnylam Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006400","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["FOR2722"],"award-info":[{"award-number":["FOR2722"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Hereditary transthyretin\u2010mediated amyloidosis is a treatable condition caused by amyloidogenic variants in the <jats:italic>transthyretin<\/jats:italic>\u2010gene resulting in severe peripheral neuropathy or cardiomyopathy. Only about a third of over 130 known variants are clearly pathogenic, most are classified as variants of uncertain significance. A clear delineation of these into pathogenic or non\u2010pathogenic is highly desirable but hampered by low frequency and penetrance. We thus sought to characterize their amylogenic potential by an unbiased in\u00a0vitro approach.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Thioflavin T and turbidity assays were used to compare the potential of mammalian cell expressed wt\u2010transthyretin and 12 variant proteins (either variants of uncertain significance, benign, pathogenic) to aggregate and produce amyloid fibrils in\u00a0vitro. As proof of principle, the assays were applied to transthyretin\u2010Ala65Val, a variant that was newly detected in a family with peripheral neuropathy and amyloid deposits in biopsies. In silico analysis was performed to compare the position of the benign and pathogenic variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Transthyretin\u2010Ala65Val showed a significantly higher amyloidogenic potential than wt\u2010transthyretin, in both turbidity\u2010 and Thioflavin T\u2010assays, comparable to known pathogenic variants. The other eight tested variants did not show an increased amyloidogenic potential. In silico structural analysis further confirmed differences between pathogenic and benign variants in position and interactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We propose a biochemical approach to assess amyloidogenic potential of transthyretin variants. As exemplified by transthyretin\u2010Ala65Val, data of three assays together with histopathology clearly demonstrates its amyloidogenicity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51626","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T08:04:41Z","timestamp":1659081881000},"page":"1252-1263","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Amyloidogenicity assessment of transthyretin gene variants"],"prefix":"10.1002","volume":"9","author":[{"given":"Nicolai B.","family":"Grether","sequence":"first","affiliation":[{"name":"Department of Neurology Faculty of Medicine and University Hospital of Cologne, University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felix","family":"Napravnik","sequence":"additional","affiliation":[{"name":"Department of Neurology Faculty of Medicine and University Hospital of Cologne, University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Imhof","sequence":"additional","affiliation":[{"name":"Institute for Dental Research and Oral Musculoskeletal Biology and Center for Biochemistry University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinhold P.","family":"Linke","sequence":"additional","affiliation":[{"name":"Reference Center of Amyloid Diseases  Munich Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan H.","family":"Br\u00e4sen","sequence":"additional","affiliation":[{"name":"Nephropathology Unit Institute of Pathology, Hannover Medical School  Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Nephropathology Unit Institute of Pathology, Hannover Medical School  Hannover Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maike","family":"Dohrn","sequence":"additional","affiliation":[{"name":"Department of Neurology Medical Faculty of the RWTH Aachen University Aachen  Germany"},{"name":"Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics University of Miami, Miller School of Medicine  Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Neurology Faculty of Medicine and University Hospital of Cologne, University of Cologne  Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin K. 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