| Structural highlights
Disease
TTHY_HUMAN Defects in TTR are the cause of amyloidosis transthyretin-related (AMYL-TTR) [MIM:105210. A hereditary generalized amyloidosis due to transthyretin amyloid deposition. Protein fibrils can form in different tissues leading to amyloid polyneuropathies, amyloidotic cardiomyopathy, carpal tunnel syndrome, systemic senile amyloidosis. The disease includes leptomeningeal amyloidosis that is characterized by primary involvement of the central nervous system. Neuropathologic examination shows amyloid in the walls of leptomeningeal vessels, in pia arachnoid, and subpial deposits. Some patients also develop vitreous amyloid deposition that leads to visual impairment (oculoleptomeningeal amyloidosis). Clinical features include seizures, stroke-like episodes, dementia, psychomotor deterioration, variable amyloid deposition in the vitreous humor.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] Defects in TTR are a cause of hyperthyroxinemia dystransthyretinemic euthyroidal (HTDE) [MIM:145680. It is a condition characterized by elevation of total and free thyroxine in healthy, euthyroid persons without detectable binding protein abnormalities.[73] Defects in TTR are a cause of carpal tunnel syndrome type 1 (CTS1) [MIM:115430. It is a condition characterized by entrapment of the median nerve within the carpal tunnel. Symptoms include burning pain and paresthesias involving the ventral surface of the hand and fingers which may radiate proximally. Impairment of sensation in the distribution of the median nerve and thenar muscle atrophy may occur. This condition may be associated with repetitive occupational trauma, wrist injuries, amyloid neuropathies, rheumatoid arthritis.[74]
Function
TTHY_HUMAN Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.[75]
Publication Abstract from PubMed
Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state-thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration.
Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors.,Connelly S, Mortenson DE, Choi S, Wilson IA, Powers ET, Kelly JW, Johnson SM Bioorg Med Chem Lett. 2017 Aug 1;27(15):3441-3449. doi:, 10.1016/j.bmcl.2017.05.080. Epub 2017 May 26. PMID:28625364[76]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
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- ↑ Murakami T, Maeda S, Yi S, Ikegawa S, Kawashima E, Onodera S, Shimada K, Araki S. A novel transthyretin mutation associated with familial amyloidotic polyneuropathy. Biochem Biophys Res Commun. 1992 Jan 31;182(2):520-6. PMID:1734866
- ↑ Murakami T, Atsumi T, Maeda S, Tanase S, Ishikawa K, Mita S, Kumamoto T, Araki S, Ando M. A novel transthyretin mutation at position 30 (Leu for Val) associated with familial amyloidotic polyneuropathy. Biochem Biophys Res Commun. 1992 Aug 31;187(1):397-403. PMID:1520326
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- ↑ Bergen HR 3rd, Zeldenrust SR, Butz ML, Snow DS, Dyck PJ, Dyck PJ, Klein CJ, O'Brien JF, Thibodeau SN, Muddiman DC. Identification of transthyretin variants by sequential proteomic and genomic analysis. Clin Chem. 2004 Sep;50(9):1544-52. Epub 2004 Jun 24. PMID:15217993 doi:10.1373/clinchem.2004.033266
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- ↑ Bergstrom J, Patrosso MC, Colussi G, Salvadore M, Penco S, Lando G, Marocchi A, Ueda A, Nakamura M, Ando Y. A novel type of familial transthyretin amyloidosis, ATTR Asn124Ser, with co-localization of kappa light chains. Amyloid. 2007 Jun;14(2):141-5. PMID:17577687 doi:779687106
- ↑ Altland K, Benson MD, Costello CE, Ferlini A, Hazenberg BP, Hund E, Kristen AV, Linke RP, Merlini G, Salvi F, Saraiva MJ, Singer R, Skinner M, Winter P. Genetic microheterogeneity of human transthyretin detected by IEF. Electrophoresis. 2007 Jun;28(12):2053-64. PMID:17503405 doi:10.1002/elps.200600840
- ↑ Augustin S, Llige D, Andreu A, Gonzalez A, Genesca J. Familial amyloidosis in a large Spanish kindred resulting from a D38V mutation in the transthyretin gene. Eur J Clin Invest. 2007 Aug;37(8):673-8. PMID:17635579 doi:ECI1836
- ↑ Moses AC, Rosen HN, Moller DE, Tsuzaki S, Haddow JE, Lawlor J, Liepnieks JJ, Nichols WC, Benson MD. A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J Clin Invest. 1990 Dec;86(6):2025-33. PMID:1979335 doi:http://dx.doi.org/10.1172/JCI114938
- ↑ Murakami T, Tachibana S, Endo Y, Kawai R, Hara M, Tanase S, Ando M. Familial carpal tunnel syndrome due to amyloidogenic transthyretin His 114 variant. Neurology. 1994 Feb;44(2):315-8. PMID:8309582
- ↑ Herbert J, Wilcox JN, Pham KT, Fremeau RT Jr, Zeviani M, Dwork A, Soprano DR, Makover A, Goodman DS, Zimmerman EA, et al.. Transthyretin: a choroid plexus-specific transport protein in human brain. The 1986 S. Weir Mitchell award. Neurology. 1986 Jul;36(7):900-11. PMID:3714052
- ↑ Connelly S, Mortenson DE, Choi S, Wilson IA, Powers ET, Kelly JW, Johnson SM. Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors. Bioorg Med Chem Lett. 2017 Aug 1;27(15):3441-3449. doi:, 10.1016/j.bmcl.2017.05.080. Epub 2017 May 26. PMID:28625364 doi:http://dx.doi.org/10.1016/j.bmcl.2017.05.080
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