{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T14:24:14Z","timestamp":1780928654121,"version":"3.54.1"},"reference-count":36,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health, Labour and Welfare SciencesResearch","award":["23FC1035"],"award-info":[{"award-number":["23FC1035"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Over 150 transthyretin (TTR) mutations have been identified in hereditary transthyretin (ATTRv) amyloidosis, and new TTR variants have recently emerged. However, the pathogenicity of several new variants remains unclear, making it important to elucidate the differences between amyloidogenic and wild-type TTR. In this study, we report a novel TTR variant (V121A) identified in two unrelated amyloidosis patients aged &gt; 60 years who developed cardiomyopathy. We evaluated the detailed biochemical features of this TTR variant to confirm its amyloidogenicity using plasma samples from these patients and recombinant TTR proteins. While the V121A TTR variant has a similar ability to assemble into a tetramer as wild-type TTR, it aggregates more readily over a wide potential hydrogen range than wild-type TTR. Additionally, the V121A variant is highly prone to dissociation and resistant to binding with known TTR tetramer stabilizers. Clinical and biochemical data suggest that this novel variant is clearly pathogenic, is highly prone to dissociation and aggregation, and is associated with the development of late-onset amyloid cardiomyopathy. Interestingly, amyloid fibril formation due to this variant may not be affected by known TTR stabilizers.<\/jats:p>","DOI":"10.3390\/ijms26104659","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T09:26:48Z","timestamp":1747128408000},"page":"4659","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Clinical and Biochemical Characterization of Hereditary ATTR Amyloidosis Caused by a Novel Transthyretin Variant V121A (p.V141A)"],"prefix":"10.3390","volume":"26","author":[{"given":"Tsuneaki","family":"Yoshinaga","sequence":"first","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"},{"name":"Department of Neurology and Rheumatology, Shinshu University, Matsumoto 390-8621, Japan"},{"name":"Institute for Biomedical Sciences, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuuki","family":"Yoshioka","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tachikawa General Hospital, Nagaoka 940-0831, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3425-8697","authenticated-orcid":false,"given":"Felix J.","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1581-6382","authenticated-orcid":false,"given":"Ming","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryota","family":"Ito","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Tachikawa General Hospital, Nagaoka 940-0831, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eri","family":"Ishikawa","sequence":"additional","affiliation":[{"name":"Division of Instrumental Research, Research Center for Advanced Science and Technology, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9125-7001","authenticated-orcid":false,"given":"Fuyuki","family":"Kametani","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Sciences, Shinshu University, Matsumoto 390-8621, Japan"},{"name":"Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-0057, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuzi","family":"Aoyagi","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Tachikawa General Hospital, Nagaoka 940-0831, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5076-2052","authenticated-orcid":false,"given":"Takahiro","family":"Okumura","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toyoaki","family":"Murohara","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5520-6530","authenticated-orcid":false,"given":"Masahide","family":"Yazaki","sequence":"additional","affiliation":[{"name":"Institute for Biomedical Sciences, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiki","family":"Sekijima","sequence":"additional","affiliation":[{"name":"Department of Neurology and Rheumatology, Shinshu University, Matsumoto 390-8621, Japan"},{"name":"Institute for Biomedical Sciences, Shinshu University, Matsumoto 390-8621, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1016\/j.jacc.2019.04.003","article-title":"Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review","volume":"73","author":"Ruberg","year":"2019","journal-title":"J. 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