Sequence

Analysis Tool	Result
iMutant 3.0	Destabilizing
STRUM	Destabilizing
iStable	Destabilizing
Provean	Neutral
PredictSNP	Deleterious
PhD-SNP	Deleterious
PolyPhen-2	Deleterious
SIFT	Deleterious
FATHMM	Damaging

Structure

Analysis Tool	Result
mCSM	Destabilizing
SDM	Destabilizing
DUET	Destabilizing
DynaMut	Destabilizing
CUPSAT	Destabilizing
ENCoM	Destabilizing
FoldX (Protein Stability)	Reduces

Aggregation

Analysis Tool	Result
TANGO (Aggregation Tendency)	No effect
WALTZ (Amyloid Propensity)	No effect
LIMBO (Chaperone Binding Tendency)	No effect

Reported Articles

• Altland K, Benson MD, Costello CE, Ferlini A, Hazenberg BPC, Hund E, et al. Genetic microheterogeneity of human transthyretin detected by IEF. ELECTROPHORESIS. 2007;28: 2053–2064. doi:10.1002/elps.200600840
• Dwulet FE and Benson MD. (1983). Polymorphisms of human plasma thyroxine binding prealbumin. Biochem Biophys Res Commun. 114:657-662.
• Saraiva MJ, Costa PP, Birken S, and Goodman DS. (1983). Presence of an abnormal transthyretin (prealbumin) in Portuguese patients with familial amyloidotic polyneuropathy. Trans Assoc Am Physicians. 96:261-270.
• Tawara S, Nakazato M, Kangawa K, Matsuo H, and Araki S. (1983). Identification of amyloid prealbumin variant in familial amyloidotic polyneuropathy (Japanese type). Biochem Biophys Res Commun. 116:880-888.
• Nakazato M, Kangawa K, Minamino N, Tawara S, Matsuo H, and Araki S. (1984). Identification of a prealbumin variant in the serum of a Japanese patient with familial amyloidotic polyneuropathy. Biochem Biophys Res Commun. 122:712-718.
• Lemos C, Coelho T, Alves-Ferreira M, Santos D, Sequeiros J, Sousa A. Unravelling the epidemiology of late-onset and asymptomatic carriers of FAP ATTR V30M in a Portuguese population. Orphanet J Rare Dis. 2015;10: O3. doi:10.1186/1750-1172-10-S1-O3
• Santos D, Coelho T, Alves-Ferreira M, Sequeiros J, Alonso I, Grazina M, et al. The hidden story behind gender differences in familial amyloid polyneuropathy (FAP) ATTRV30M. Orphanet J Rare Dis. 2015;10: O4. doi:10.1186/1750-1172-10-S1-O4
• Koike H, Ikeda S, Takahashi M, Kawagashira Y, Iijima M, Katsuno M, et al. Vasculopathy in transthyretin Val30Met familial amyloid polyneuropathy. Orphanet J Rare Dis. 2015;10: O11. doi:10.1186/1750-1172-10-S1-O11
• Conceição I, Silva C, Costa M, Castro J. Neurophysiological pitfalls in TTR-FAP Val30Met. Orphanet J Rare Dis. 2015;10: O12. doi:10.1186/1750-1172-10-S1-O12
• Ueda M, Yamashita T, Misumi Y, Masuda T, Ando Y. Origin of sporadic late-onset hereditary ATTR Val30Met amyloidosis in Japan. Amyloid. 2018;25: 143–147. doi:10.1080/13506129.2018.1531842

Studies on Therapeutic Strategy*

• Hosoi A, Su Y, Torikai M, Jono H, Ishikawa D, Soejima K, et al. Novel Antibody for the Treatment of Transthyretin Amyloidosis. J Biol Chem. 2016;291: 25096–25105. doi:10.1074/jbc.M116.738138
• Gonçalves P, Martins H, Costelha S, Maia LF, Saraiva MJ. Efficiency of silencing RNA for removal of transthyretin V30M in a TTR leptomeningeal animal model. Amyloid. 2016;23: 249–253. doi:10.1080/13506129.2016.1256282
• Tojo K, Sekijima Y, Kelly JW, Ikeda S. Diflunisal stabilizes familial amyloid polyneuropathy-associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Neuroscience Research. 2006;56: 441–449. doi:10.1016/j.neures.2006.08.014
• Coelho T, Maia LF, Martins da Silva A, Waddington Cruz M, Planté-Bordeneuve V , Lozeron P, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79: 785–792. doi:10.1212/WNL.0b013e3182661eb1
• Kurosawa T, Igarashi S, Nishizawa M, Onodera O. Selective silencing of a mutant transthyretin allele by small interfering RNAs. Biochem Biophys Res Commun. 2005;337: 1012–1018. doi:10.1016/j.bbrc.2005.09.142
• Coelho T, Adams D, Silva A, Lozeron P, Hawkins PN, Mant T, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369: 819–829. doi:10.1056/NEJMoa1208760
• Cardoso I, Martins D, Ribeiro T, Merlini G, Saraiva MJ. Synergy of combined doxycycline/TUDCA treatment in lowering Transthyretin deposition and associated biomarkers: studies in FAP mouse models. J Transl Med. 2010;8: 74. doi:10.1186/1479-5876-8-74
• Benson MD, Waddington-Cruz M, Berk JL, Polydefkis M, Dyck PJ, Wang AK, et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379: 22–31. doi:10.1056/NEJMoa1716793
• Adams D, Gonzalez-Duarte A, O’Riordan WD, Yang C-C, Ueda M, Kristen AV, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379: 11–21. doi:10.1056/NEJMoa1716153

*includes studies on model organisms and commercially unavailable drugs

Available PDB Structures

• 4PWE
• 4TL4