Transthyretin and the Transthyretin Amyloidoses

  • Joel N. Buxbaum
Part of the Protein Reviews book series (PRON, volume 6)


Transthyretin is a normal serum protein that carries the secondary thyroid hormone thyroxine and retinol binding protein when it is loaded with retinol. It is synthesized primarily in the liver but there is also significant production in the choroid plexus and the retina. Both message and protein are found in the kidney but that site does not appear to contribute to the serum level in any meaningful way. The protein is a homotetramer composed of the 14-kDa monomer with the thyroxine binding sites in the central groove. The structure is highly conserved particularly in the regions responsible for ligand binding, suggesting that its carrier function has been retained over the millennia. More than 80 mutations at 55 different positions in the gene encoding the protein are the primary cause of a set of human disorders collectively known as the familial amyloidotic polyneuropathies and cardiomyopathies. In these diseases, the soluble protein becomes insoluble under physiologic conditions resulting in functional compromise in the organs in which the protein is deposited. Peripheral nerves, heart, kidneys, gastrointestinal tract, and the leptomeninges have all been described as sites of deposition. It is possible that particular syndromes are associated with particular sets of mutations but, because of the rarity of some of the mutations, it is uncertain if the relationship between any mutation and any clinical syndrome is absolute. Further, it is also clear that the wild-type protein can deposit in tissues with subsequent dysfunction, particularly in the heart and carpal tunnel. Biophysical studies in vitro indicate that the process leading from soluble tetramer to insoluble aggregates involves monomer release, misfolding, oligomerization, and extension and lateral aggregation apparently as a downhill polymerization to a more stable lower energy state. How this is modulated in vivo is not known, although accessory molecules appear to be involved in the process. The early, albeit incomplete, understanding of the processes have led to potential therapies directed at stabilizing the tetramer or interfering with the interaction with other molecules as well as replacing the offending gene by liver transplantation.


Familial Amyloid Polyneuropathy Familial Amyloidotic Polyneuropathy Transthyretin Amyloidosis Senile Systemic Amyloidosis Retinol Binding Protein Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adamski-Werner, S. L., Palaninathan, S. K., Sacchettini, J. C., and Kelly, J. W. (2004). Diflunisal analogues stabilize the native state of transthyretin. Potent inhibition of amyloidogenesis. J. Med. Chem. 47:355–374.PubMedCrossRefGoogle Scholar
  2. Almeida, M. R., Alves, I. L., Terazaki, H., Ando, Y., and Saraiva, M. J. (2000). Comparative studies of two transthyretin variants with protective effects on familial amyloidotic polyneuropathy: TTR R104H and TTR T119M. Biochem. Biophys. Res. Commun. 270:1024–1028.PubMedCrossRefGoogle Scholar
  3. Andersson, K., Olofsson, A., Nielsen, E. H., Svehag, S. E., and Lundgren, E. (2002). Only amyloidogenic intermediates of transthyretin induce apoptosis. Biochem. Biophys. Res. Commun. 294:309–314.PubMedCrossRefGoogle Scholar
  4. Ando, Y., Ikegawa, S., Miyazaki, A., Inoue, M., Morino, Y., and Araki, S. (1989). Role of variant prealbumin in the pathogenesis of familial amyloidotic polyneuropathy: fate of normal and variant prealbumin in the circulation. Arch. Biochem. Biophys. 274:87–93.PubMedCrossRefGoogle Scholar
  5. Ando, Y., Nyhlin, N., Suhr, O., Holmgren, G., Uchida, K., el, S., Yamashita, T., Terasaki, H., Nakamura, M., Uchino, M., and Ando, M. (1997). Oxidative stress is found in amyloid deposits in systemic amyloidosis. Biochem. Biophys. Res. Commun. 232:497–502.PubMedCrossRefGoogle Scholar
  6. Ando, Y., Ando, E., Ohlsson, P. I., Olofsson, A., Sandgren, O., Suhr, O., Terazaki, H., Obayashi, K., Lundgren, E., Ando, M., and Negi, A. (1999). Analysis of transthyretin amyloid fibrils from vitreous samples in familial amyloidotic polyneuropathy (Val30Met). Amyloid Int. J. Exp. Clin. Invest. 6:119–123.Google Scholar
  7. Andrade, C. (1952). A peculiar form of peripheral neuropathy. Familial atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75:408–427.PubMedCrossRefGoogle Scholar
  8. Askanas, V., Engel, W. K., Alvarez, R. B., Frangione, B., Ghiso, J., and Vidal, R. (2000). Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and transthyretin Val122Ile allele. Ann. Neurol. 47:544–549.PubMedCrossRefGoogle Scholar
  9. B.U.M.C. (Boston University Medical Campus), Boston (February 3, 2004). Available at Scholar
  10. Bellovino, D., Morimoto, T., Tosetti, F., and Gaetani, S. (1996). Retinol binding protein and transthyretin are secreted as a complex formed in the endoplasmic reticulum in HepG2 human hepatocarcinoma cells. Exp. Cell Res. 222:77–83.PubMedCrossRefGoogle Scholar
  11. Bellovino, D., Morimoto, T., Pisaniello, A., and Gaetani, S. (1998). In vitro and in vivo studies on transthyretin oligomerization. Exp. Cell Res. 243:101–112.PubMedCrossRefGoogle Scholar
  12. Benson, M. D. and Dwulet, F. E. (1983). Prealbumin and retinol binding protein serum concentrations in the Indiana type hereditary amyloidosis. Arthritis Rheum. 26:1493–1498.PubMedCrossRefGoogle Scholar
  13. Bergstrom, J., Gustavsson, A., Hellman, U., Sletten, K., Murphy, C. L., Weiss, D. T., Solomon, A., Olofsson, B. O., and Westermark, P. (2005). Amyloid deposits in transthyretin-derived amyloidosis: cleaved transthyretin is associated with distinct amyloid morphology. J. Pathol. 206(2): 224–232.PubMedCrossRefGoogle Scholar
  14. Blake, C. C. and Oatley, S. J. (1977). Protein-DNA and protein-hormone interactions in prealbumin: a model of the thyroid hormone nuclear receptor? Nature 268:115–120.PubMedCrossRefGoogle Scholar
  15. Blake, C. C. F., Geisow, M. J., and Oatley, S. J. (1978). Structure of prealbumin: secondary, tertiary and quaternary interactions determined by Fourier refinement at 1.8 Å. J. Mol. Biol. 121:339–356.PubMedCrossRefGoogle Scholar
  16. Brett, M., Persey, M. R., Reilly, M. M., Revesz, T., Booth, D. R., Booth, S. E., Hawkins, P. N., Pepys, M. B., and Morgan-Hughes, J. A. (1999). Transthyretin Leu12Pro is associated with systemic, neuropathic and leptomeningeal amyloidosis. Brain 122:183–190.PubMedCrossRefGoogle Scholar
  17. Brugler, L., Stankovic, A., Bernstein, L., Scott, F., and O’Sullivan-Maillet, J. (2002). The role of visceral protein markers in protein calorie malnutrition. Clin. Chem. Lab. Med. 40:1360–1369.PubMedCrossRefGoogle Scholar
  18. Cardoso, I., Merlini, G., and Saraiva, M. J. (2003). 4′-iodo-4′-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. FASEB J. 17:803–809.PubMedCrossRefGoogle Scholar
  19. Chevalier, S., Blaner, W. S., Azais-Braesco, V., and Tuchweber, B. (1999). Dietary restriction alters retinol and retinolbinding protein metabolism in aging rats. J. Gerontol. A Biol. Sci. Med. Sci. 54:B384–B392.PubMedGoogle Scholar
  20. Chou, C. T., Lee, C. C., Chang, D. M., Buxbaum, J. N., and Jacobson, D. R. (1997). Familial amyloidosis in one Chinese family: clinical, immunological, and molecular genetic analysis. J. Intern. Med. 241:327–331.PubMedCrossRefGoogle Scholar
  21. Coelho, T., Carvalho, M., Saraiva, M., Alves, I., Almeida, M. R., and Costa, P. P. (1993). A strikingly benign evolution of FAP in an individual found to be a compound heterozygote for two TTR mutations: TTR MET 30 and TTR MET 119. J. Rheumatol. 20:179.Google Scholar
  22. Connors, L. H., Karbassi, J., Lim, A., Costello, C. E., and Skinner, M. (2002). Senile cardiac amyloidosis: serum levels of S-sulfated transthyretin (abs). The 5th International Symposium on Familial Amyloidotic Polyneuropathy and other Transthyretin Related Disorders. 23.9-24-2002. Boston University. The 5th International Symposium on Familial Amyloidotic Polyneuropathy and Other Transthyretin Related Disorders.Google Scholar
  23. Connors, L. H., Lim, A., Prokaeva, T., Roskens, V. A., and Costello, C. E. (2003). Tabulation of human transthyretin (TTR) variants, 2003. Amyloid 10:160–184.PubMedGoogle Scholar
  24. Cooper, D. N. and Youssoufian, H. (1988). The CpG dinucleotide and human genetic disease. Hum. Genet. 78:151–155.PubMedCrossRefGoogle Scholar
  25. Cornwell, G. G., III, Murdoch, W. L., Kyle, R. A., Westermark, P., and Pitkanen, P. (1983). Frequency and distribution of senile cardiovascular amyloid. A clinicopathologic correlation. Am. J. Med. 75:618–623.PubMedCrossRefGoogle Scholar
  26. Costa, R. H., Van Dyke, T. A., Yan, C., Kuo, F., and Darnell, J. E., Jr. (1990). Similarities in transthyretin gene expression and differences in transcription factors: liver and yolk sac compared to choroid plexus. Proc. Natl. Acad. Sci USA 87:6589–6593.PubMedCrossRefGoogle Scholar
  27. Dickson, P. W., Howlett, G. J., and Schreiber, G. (1985). Rat transtyhretin (prealbumin). J. Biol. Chem. 260:8214–8219.PubMedGoogle Scholar
  28. Divino, C. M. and Schussler, G. C. (1990). Receptor-mediated uptake and internalization of transthyretin. J. Biol Chem. 265:1425–1429.PubMedGoogle Scholar
  29. Eneqvist, T., Lundberg, E., Nilsson, L., Abagyan, R., and Sauer-Eriksson, A. E. (2003). The transthyretin-related protein family. Eur. J. Biochem. 270:518–532.PubMedCrossRefGoogle Scholar
  30. Falk, R. H., Plehn, J. F., Deering, T., Shick, E. C. J., Bosnay, P., Rubinow, A., Skinner, M., and Cohen, A. S. (1987). Sensitivity and specificity of the echocardiographic features of cardiac amyloidosis. Am. J. Cardiol. 59:418–422.PubMedCrossRefGoogle Scholar
  31. Filteau, S. M. (2000). Use of the retinol-binding protein: transthyretin ratio for assessment of vitamin A status during the acute-phase response. Br. J. Nutr. 83:513–520.PubMedGoogle Scholar
  32. Fitch, N. J. S., Akbari, M. T., and Ramsden, D. B. (1991). An inherited non-amyloidogenic transthyretin variant, [Ser6]-TTR, with increased thyroxine-binding affinity, characterized by DNA sequencing. J. Endocrinol. 129:309–313.PubMedGoogle Scholar
  33. Gallo, G., Picken, M., Frangione, B., and Buxbaum, J. (1988). Nonamyloidotic monoclonal immunoglobulin deposits lack amyloid P component. Mod. Pathol. 1:453–456.PubMedGoogle Scholar
  34. Gallo, G., Wisniewski, T., Choi-Miura, N. H., Ghiso, J., and Frangione, B. (1994). Potential role of apolipoprotein-E in fibrillogenesis. Am. J. Pathol. 145:526–530.PubMedGoogle Scholar
  35. Getz, R. K., Kennedy, B. G., and Mangini, N. J. (1999). Transthyretin localization in cultured and native human retinal pigment epithelium. Exp. Eye Res. 68:629–636.PubMedCrossRefGoogle Scholar
  36. Goldsteins, G., Andersson, K., Olofsson, A., Dacklin, I., Edvinsson, A., Baranov, V., Sandgren, O., Thylen, C., Hammarstrom, S., and Lundgren, E. (1997). Characterization of two highly amyloidogenic mutants of transthyretin. Biochemistry 36:5346–5352.PubMedCrossRefGoogle Scholar
  37. Gonzalez, G. and Offord, R. E. (1971). The subunit structure of prealbumin. J. Biochem. 125:309–317.Google Scholar
  38. Gustavsson, Å., Jahr, H., Tobiassen, R., Jacobson, D. R., Sletten, K., and Westermark, P. (1995). Amyloid fibril composition and transthyretin gene structure in senile systemic amyloidosis. Lab. Invest. 73:703–708.PubMedGoogle Scholar
  39. H.G.M.D. (the Human Gene Mutation Database), 1984, Cardiff (May 18, 2005). Available at Scholar
  40. Hammarstrom, P., Schneider, F., and Kelly, J. W. (2001). Trans-suppression of misfolding in an amyloid disease. Science 293:2459–2462.PubMedCrossRefGoogle Scholar
  41. Hammarstrom, P., Sekijima, Y., White, J. T., Wiseman, R. L., Lim, A., Costello, C. E., Altland, K., Garzuly, F., Budka, H., and Kelly, J. W. (2003a). D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid: a prescription for central nervous system amyloidosis? Biochemistry 42:6656–6663.PubMedCrossRefGoogle Scholar
  42. Hammarstrom, P., Wiseman, R. L., Powers, E. T., and Kelly, J. W. (2003b). Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299:713–716.PubMedCrossRefGoogle Scholar
  43. Hanes, D., Zech, L. A., Murrell, J., and Benson, M. D. (1996). Metabolism of normal and MET30 transthyretin. Advanced Food Nutr. Res. 40:149–153.Google Scholar
  44. Hanyu, N., Ikeda, S., Nakadai, A., Yanagisawa, N., and Powell, H. C. (1989). Peripheral nerve pathological findings in familial amyloid polyneuropathy: A correlative study of proximal sciatic nerve and sural nerve lesions. Ann. Neurol. 25:340–350.PubMedCrossRefGoogle Scholar
  45. Harats, N., Worth, R. M., and Benson, M. D. (1989). Hereditary amyloidosis: Evidence against early amyloid deposition. Arthritis Rheum. 32:1474–1476.PubMedCrossRefGoogle Scholar
  46. Hardell, L., Holmgren, G., Steen, L., Fredrikson, M., and Axelson, O. (1995). Occupational and other risk factors for clinically overt familial amyloid polyneuropathy. Epidemiology 6:598–601.PubMedCrossRefGoogle Scholar
  47. Harkany, T., Garzuly, F., Csanaky, G., Luiten, P. G., Nyakas, C., Linke, R. P., and Viragh, S. (2002). Cutaneous lymphatic amyloid deposits in “Hungarian-type” familial transthyretin amyloidosis: a case report. Br. J. Dermatol. 146:674–679.PubMedCrossRefGoogle Scholar
  48. Herbert, J., Wilcox, J. N., Pham, K. C., Fremeau, R. T., Zaviani, M., Dwork, A., Soprano, D., Makover, A., Goodman, D. S., Zimmerman, E. Z., Roberts, J. L., and Schon, E. A. (1986). Transthyretin: a choroid plexus-specific transport protein in human brain. Neurology 36:900–911.PubMedGoogle Scholar
  49. Herlenius, G., Larsson, M., and Ericzon, B. G. (2001). FAP World Transplant Register and domino/sequential register update. Transplant. Proc. 33:1367.PubMedCrossRefGoogle Scholar
  50. Herlenius, G., Wilczek, H. E., Larsson, M., and Ericzon, B. G. (2004). Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry. Transplantation 77:64–71.PubMedCrossRefGoogle Scholar
  51. Herrick, M. K., DeBruyne, K., Horoupian, D. S., Skare, J., Vanefsky, M. A., and Ong, T. (1996). Massive leptomeningeal amyloidosis associated with a Val30Met transthyretin gene. Neurology 47:988–992.PubMedGoogle Scholar
  52. Hodkinson, H. M. and Pomerance, A. (1977). The clinical significance of senile cardiac amyloidosis: a prospective clinicopathological study. Q. J. Med. 46:381–387.PubMedGoogle Scholar
  53. Holmgren, G., Wikstrom, L., Lundgren, H. E., and Suhr, O. B. (2004). Discordant penetrance of the trait for familial amyloidotic polyneuropathy in two pairs of monozygotic twins. J. Intern. Med. 256:453–456.PubMedCrossRefGoogle Scholar
  54. Hurshman, A. R., White, J. T., Powers, E. T., and Kelly, J. W. (2004). Transthyretin aggregation under partially denaturing conditions is a downhill polymerization. Biochemistry 43:7365–7381.PubMedCrossRefGoogle Scholar
  55. Ii, K., Kyle, R. A., and Dyck, P. J. (1992). Immunohistochemical characterization of amyloid proteins in sural nerves and clinical associations in amyloid neuropathy. Am. J. Pathol. 141:217–226.Google Scholar
  56. Ikeda, S., Nakazato, M., Ando, Y., and Sobue, G. (2002). Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity. Neurology 58:1001–1007.PubMedGoogle Scholar
  57. Imasawa, M., Toda, Y., Sakurada, Y., Imai, M., and Iijima, H. (2004). Vitreous opacities in a case of familial amyloidotic polyneuropathy associated with a transthyretin Lys 54. Acta Ophthalmol. Scand. 82:635–636.PubMedCrossRefGoogle Scholar
  58. Ingenbleek, Y. and Young, V. R. (2002). Significance of transthyretin in protein metabolism. Clin. Chem. Lab. Med. 40:1281–1291.PubMedCrossRefGoogle Scholar
  59. Ishida, M., Kajita, Y., Ochi, Y., Hachiya, T., Miyazaki, T., Yoshimura, M., and Ijichi, H. (1982). Measurement of serum thyroxine binding prealbumin in various thyroidal states by radioimmunoassay. Endocrinol. Jpn. 29:607–613.PubMedGoogle Scholar
  60. Jacobson, D. R., McFarlin, D. E., Kane, I., and Buxbaum, J. N. (1992). Transthyretin Pro55, a variant associated with earlyonset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement. Hum. Genet. 89:353–356.PubMedCrossRefGoogle Scholar
  61. Jacobson, D. R., Alves, I. L., Saraiva, M. J., Thibodeau, S. N., and Buxbaum, J. N. (1995). Transthyretin Ser 6 gene frequency in individuals without amyloidosis. Hum. Genet. 95:308–312.PubMedCrossRefGoogle Scholar
  62. Jacobson, D. R., Pastore, R. D., Yaghoubian, R., Kane, I., Gallo, G., Buck, F. S., and Buxbaum, J. N. (1997). Variantsequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N. Engl. J. Med. 336:466–473.PubMedCrossRefGoogle Scholar
  63. Jacobsson, B. (1989). Localization of transthyretin-mRNA and of immunoreactive transthyretin in the human fetus. Virchows Arch. A Pathol. Anat. 415:259–263.CrossRefGoogle Scholar
  64. Jacobsson, B., Collins, V. P., Grimelius, L., Pettersson, T., Sandstedt, B., and Carlstrom, A. (1989). Transthyretin immunoreactivity in human and porcine liver, choroid plexus, and pancreatic islets. J. Histochem. Cytochem. 37:31–37.PubMedGoogle Scholar
  65. Jarrett, J. T. and Lansbury, P. T., Jr. (1993). Seeding “one-dimensional crystallization” of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie. Cell 73:1055–1058.PubMedCrossRefGoogle Scholar
  66. Kanda, Y., Goodman, D. S., Canfield, R. E., and Morgan, F. J. (1974). The amino acid sequence of human plasma prealbumin. J Biol. Chem. 249:6796–6805.PubMedGoogle Scholar
  67. Kaufman, H. E. and Thomas, L. B. (1959). Vitreous opacities diagnostic of familial primary amyloidosis. N. Engl. J. Med. 261:1267–1271.PubMedGoogle Scholar
  68. Kelly, J. W. (1998). The alternative conformations of amyloidogenic proteins and their multi-step assembly pathways. Curr. Opin. Struct. Biol. 8:101–106.PubMedCrossRefGoogle Scholar
  69. Kisilevsky, R., Szarek, W. A., Ancsin, J., Vohra, R., Li, Z., and Marone, S. (2004). Novel glycosaminoglycan precursors as antiamyloid agents: part IV. J. Mol. Neurosci. 24:167–172.PubMedCrossRefGoogle Scholar
  70. Kohno, K., Palha, J. A., Miyakawa, K., Saraiva, M. J., Ito, S., Mabuchi, T., Blaner, W. S., Iijima, H., Tsukahara, S., Episkopou, V., Gottesman, M. E., Shimada, K., Takahashi, K., Yamamura, K., and Maeda, S. (1997). Analysis of amyloid deposition in a transgenic mouse model of homozygous familial amyloidotic polyneuropathy. Am. J. Pathol. 150:1497–1508.PubMedGoogle Scholar
  71. Kuchler-Bopp, S., Dietrich, J. B., Zaepfel, M., and Delaunoy, J. P. (2000). Receptor-mediated endocytosis of transthyretin by ependymoma cells. Brain Res. 870:185–194.PubMedCrossRefGoogle Scholar
  72. Kyle, R. A., Gertz, M. A., and Linke, R. P. (1992). Amyloid localized to tenosynovium at carpal tunnel release. Immunohistochemical identification of amyloid type. Am. J. Clin. Pathol. 97:250–253.PubMedGoogle Scholar
  73. Levine, R. L. and Stadtman, E. R. (1996). Protein modifications with aging. In: E. L. Schneider & J. W. Rowe (Eds.), Handbook of the biology of aging (pp. 184–197). San Diego, Calif.; London: Academic Press.Google Scholar
  74. Lie, J. T. and Hammond, P. I. (1988). Pathology of the senescent heart: anatomic observations on 237 autopsy studies of patients 90 to 105 years old. Mayo Clinic Proc. 63:552–564.Google Scholar
  75. Lobato, L., Ventura, A., Beirao, I., Miranda, H. P., Seca, R., Henriques, A. C., Teixeira, M., Sarmento, A. M., and Pereira, M. C. (2003). End-stage renal disease in familial amyloidosis ATTR Val30Met: a definitive indication to combined liverkidney transplantation. Transplant. Proc. 35:1116–1120.PubMedCrossRefGoogle Scholar
  76. Longo, A. I., Hays, M. T., and Saraiva, M. J. (1997). Comparative stability and clearance of [Met30]transthyretin and [Met119]transthyretin. Eur. J. Biochem. 249:662–668.CrossRefGoogle Scholar
  77. Makover, A., Moriwaki, H., Ramakrishnan, R., Saraiva, M. J., Blaner, W. S., and Goodman, D. S. (1988). Plasma transthyretin. Tissue sites of degradation and turnover in the rat. J. Biol. Chem. 263:8598–8603.PubMedGoogle Scholar
  78. Marchi, N., Fazio, V., Cucullo, L., Kight, K., Masaryk, T., Barnett, G., Vogelbaum, M. A., Kinter, M., Rasmussen, P., Mayberg, M. R., and Janigro, D. (2003). Serum transthyretin monomer as a possible marker of blood-to-CSF barrier disruption. J. Neurosci. 23:1949–1955.PubMedGoogle Scholar
  79. Melhus, H., Nilsson, T., Peterson, P. A., and Rask, L. (1991). Retinol-binding protein and transthyretin expressed in HeLa cells form a complex in the endoplasmic reticulum in both the absence and presence of retinol. Exp. Cell Res. 197:119–124.PubMedCrossRefGoogle Scholar
  80. Merlini, G., Anesi, E., Garini, P., Perfetti, V., Obici, L., Ascari, E., Lechuga, M. H., Capri, G., and Gianni, L. (1999). Treatment of AL amyloidosis with 4′-iodo-4′-deoxydoxorubicin: an update [letter]. Blood 93:1112–1113.PubMedGoogle Scholar
  81. Munar-Ques, M., Pedrosa, J. L., Coelho, T., Gusmao, L., Seruca, R., Amorim, A., and Sequeiros, J. (1999). Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30. J. Med. Genet. 36:629–632.PubMedGoogle Scholar
  82. Nardo, B., Beltempo, P., Bertelli, R., Montalti, R., Vivarelli, M., Cescon, M., Grazi, G. L., Salvi, F., Magelli, C., Grigioni, F., Arpesella, G., Martinelli, G., and Cavallari, A. (2004). Combined heart and liver transplantation in four adults with familial amyloidosis: experience of a single center. Transplant. Proc. 36:645–647.PubMedCrossRefGoogle Scholar
  83. Neumann, P., Cody, V., and Wojtczak, A. (2001). Structural basis of negative cooperativity in transthyretin. Acta Biochim. Pol. 48:867–875.PubMedGoogle Scholar
  84. Noguchi, H., Ohta, M., Wakasugi, S., Noguchi, K., Nakamura, N., Nakamura, O., Miyakawa, K., Takeya, M., Suzuki, M., Nakagata, N., Urano, T., Ono, T., and Yamamura, K. (2002). Effect of the intestinal flora on amyloid deposition in a transgenic mouse model of familial amyloidotic polyneuropathy. Exp. Anim. 51:309–316.PubMedCrossRefGoogle Scholar
  85. Noy, N., Slosberg, E., and Scarlata, S. (1992). Interactions of retinol with binding proteins: Studies with retinol-binding protein and with transthyretin. Biochemistry 31:11118–11124.PubMedCrossRefGoogle Scholar
  86. Palha, J. A. (2002). Transthyretin as a thyroid hormone carrier: function revisited. Clin. Chem. Lab. Med. 40:1292–1300.PubMedCrossRefGoogle Scholar
  87. Pepys, M. B., Herbert, J., Hutchinson, W. L., Tennent, G. A., Lachmann, H. J., Gallimore, J. R., Lovat, L. B., Bartfai, T., Alanine, A., Hertel, C., Hoffmann, T., Jakob-Roetne, R., Norcross, R. D., Kemp, J. A., Yamamura, K., Suzuki, M., Taylor, G. W., Murray, S., Thompson, D., Purvis, A., Kolstoe, S., Wood, S. P., and Hawkins, P. N. (2002). Targeted pharmacological depletion of serum amyloid P component for treatment of human amyloidosis. Nature 417:254–259.PubMedCrossRefGoogle Scholar
  88. Potter, M. A. and Luxton, G. (2002). Transthyretin measurement as a screening tool for protein calorie malnutrition in emergency hospital admissions. Clin. Chem. Lab. Med. 40:1349–1354.CrossRefGoogle Scholar
  89. Qiu, H., Shimada, K., and Cheng, Z. (1992). Chromosomal localization of the mouse prealbumin gene (Ttr) by in situ hybridization. Cytogenet. Cell Genet. 61:186–188.PubMedGoogle Scholar
  90. Raz, A. (1969). The interaction of thyroxine with human plasma prealbumin and with the prealbumin-retinol-binding protein complex. J. Biol. Chem. 244:3230–3237.PubMedGoogle Scholar
  91. Redondo, C., Damas, A. M., Olofsson, A., Lundgren, E., and Saraiva, M. J. (2000). Search for intermediate structures in transthyretin fibrillogenesis: soluble tetrameric Tyr78Phe TTR expresses a specific epitope present only in amyloid fibrils. J. Mol. Biol. 304:461–470.PubMedCrossRefGoogle Scholar
  92. Reilly, M. M., Adams, D., Davis, M., Said, G., and Harding, A. E. (1995a). Haplotype analysis of French, British and other European patients with familial amyloid polyneuropathy (MET30 and TYR77). J. Neurol. 242:664–668.PubMedCrossRefGoogle Scholar
  93. Reilly, M. M., Staunton, H., and Harding, A. E. (1995b). Familial amyloid polyneuropathy (TTR ala 60) in north west Ireland: a clinical, genetic, and epidemiological study. J. Neurol. Neurosurg. Psych. 59:45–49.Google Scholar
  94. Reixach, N., Deechongkit, S., Jiang, X., Kelly, J. W., and Buxbaum, J. N. (2004). Tissue damage in the amyloidoses: Transthyretin monomers and non-native oligomers are the major cytotoxic species in tissue culture. Proc. Natl. Acad. Sci. USA 101:2817–2822.PubMedCrossRefGoogle Scholar
  95. Ritchie, R. F., Palomaki, G. E., Neveux, L. M., and Navolotskaia, O. (1999a). Reference distributions for the negative acutephase proteins, albumin, transferrin, and transthyretin: a comparison of a large cohort to the world’s literature. J. Clin. Lab. Anal. 13:280–286.PubMedCrossRefGoogle Scholar
  96. Ritchie, R. F., Palomaki, G. E., Neveux, L. M., Navolotskaia, O., Ledue, T. B., and Craig, W. Y. (1999b). Reference distributions for the negative acute-phase serum proteins, albumin, transferrin and transthyretin: a practical, simple and clinically relevant approach in a large cohort. J. Clin. Lab. Anal. 13:273–279.PubMedCrossRefGoogle Scholar
  97. Robbins, J. (2002). Transthyretin from discovery to now. Clin. Chem. Lab. Med. 40:1183–1190.PubMedCrossRefGoogle Scholar
  98. Rocken, C., Saeger, W., and Linke, R. P. (1994). Gastrointestinal amyloid deposits in old age. Pathol. Res. Pract. 190:641–649.PubMedGoogle Scholar
  99. Rosales, F. J. (1998). A low molar ratio of retinol binding protein to transthyretin indicates vitamin A deficiency during inflammation: studies in rats and a posterior analysis of vitamin A-supplemented children with measles. J. Nutr. 128:1681–1687.PubMedGoogle Scholar
  100. Rosen, H. N., Moses, A. C., Murrell, J. R., Liepnieks, J. J., and Benson, M. D. (1993). Thyroxine interactions with transthyretin: a comparison of 10 different naturally occurring human transthyretin variants. J. Clin. Endocrinol. Metab. 77:370–374.PubMedCrossRefGoogle Scholar
  101. Salvi, F., Salvi, G., Volpe, R., Mencucci, R., Plasmati, R., Michelucci, R., Gobbi, P., Santangelo, M., Ferlini, A., Forabosco, A., and Tassinari, C. A. (1993). Transthyretin-related TTR hereditary amyloidosis of the vitreous body: clinical and molecular characterization in two Italian families. Ophthalmol. Paediatr. Genet. 14:9–16.Google Scholar
  102. Samadani, U. and Costa, R. H. (1996). The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression. Mol. Cell Biol. 16:6273–6284.PubMedGoogle Scholar
  103. Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., Kholodenko, D., Lee, M., Liao, Z., Lieberburg, I., Motter, R., Mutter, L., Soriano, F., Shopp, G., Vasquez, N., Vandevert, C., Walker, S., Wogulis, M., Yednock, T., Games, D., and Seubert, P. (1999). Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177.PubMedCrossRefGoogle Scholar
  104. Schreiber, G., Tsykin, A., Aldred, A. R., Thomas, T., Fung, W. P., Dickson, P. W., Cole, T., Birch, H., De Jong, F. A., and Milland, J. (1989). The acute phase response in the rodent. Ann. N. Y. Acad. Sci. 557:61–85.PubMedGoogle Scholar
  105. Schreiber, G. and Richardson, S. J. (1997). The evolution of gene expression, structure and function of transthyretin. Comp. Biochem. Physiol. 116B:137–160.Google Scholar
  106. Schreiber, G. (2002). The evolutionary and integrative roles of transthyretin in thyroid hormone homeostasis. J. Endocrinol. 175:61–73.PubMedCrossRefGoogle Scholar
  107. Sekijima, Y., Tokuda, T., Kametani, F., Tanaka, K., Maruyama, K., and Ikeda, S. (2001). Serum transthyretin monomer in patients with familial amyloid polyneuropathy. Amyloid 8:257–262.PubMedGoogle Scholar
  108. Sekijima, Y., Hammarstrom, P., Matsumura, M., Shimizu, Y., Iwata, M., Tokuda, T., Ikeda, S., and Kelly, J. W. (2002). The novel highly destabilized A25T TTR variant rapidly misfolds, resulting in CNS amyloidosis-degradation of a highly amyloidogenic variant as a protective mechanism? The 5th International Symposium on Familial Amyloidotic Polyneuropathy and Other Transthyretin Related Disorders, Matsumoto, Japan 42. 9-24-2002.Google Scholar
  109. Sekijima, Y., Wiseman, R. L., Matteson, J., Hammarstrom, P., Miller, S. R., Sawkar, A. R., Balch, W. E., and Kelly, J. W. (2005). The biological and chemical basis for tissue-selective amyloid disease. Cell 121:73–85.PubMedCrossRefGoogle Scholar
  110. Skinner, M., Connors, L. H., Rubinow, A., Libbey, C., Sipe, J. D., and Cohen, A. S. (1985). Lowered prealbumin levels in patients with familial amyloid polyneuropathy (FAP) and their non-affected but at risk relatives. Am. J. Med. Sci. 289:17–21.PubMedCrossRefGoogle Scholar
  111. Skinner, M., Harding, J., Skare, I., Jones, L. A., Cohen, A. S., Milunsky, A., and Skare, J. (1992). A new transthyretin mutation associated with amyloidotic vitreous opacities. Asparagine for isoleucine at position 84. Ophthalmology 99:503–508.PubMedGoogle Scholar
  112. Soares, M. L., Buxbaum, J., Sirugo, G., Coelho, T., Sousa, A., Kastner, D., and Saraiva, M. J. (1999). Genetic anticipation in Portuguese kindreds with familial amyloidotic polyneuropathy is unlikely to be caused by triplet repeat expansions. Hum. Genet. 104:480–485.PubMedCrossRefGoogle Scholar
  113. Soares, M. L., Centola, M., Chae, J., Saraiva, M. J., and Kastner, D. L. (2003). Human transthyretin intronic open reading frames are not independently expressed in vivo or part of functional transcripts. Biochim. Biophys. Acta 1626:65–74.PubMedGoogle Scholar
  114. Soares, M. L., Coelho, T., Sousa, A., Holmgren, G., Saraiva, M. J., Kastner, D. L., and Buxbaum, J. N. (2004). Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden. Eur. J. Hum. Genet. 12:225–237.PubMedCrossRefGoogle Scholar
  115. Soares, M. L. (2005). Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease. Hum. Mol. Genet. 14:543–553.PubMedCrossRefGoogle Scholar
  116. Sousa, A., Andersson, R., Drugge, U., Holmgren, G., and Sandgren, O. (1993). Familial amyloidotic polyneuropathy in Sweden: geographical distribution, age of onset, and prevalence. Hum. Hered. 43:288–294.PubMedCrossRefGoogle Scholar
  117. Sousa, J. L., Grandela, C., Fernandez-Ruiz, J., de Miguel, R., de Sousa, L., Magalhaes, A. I., Saraiva, M. J., Sousa, N., and Palha, J. A. (2004). Transthyretin is involved in depression-like behaviour and exploratory activity. J. Neurochem. 88(5), 1052–1058.PubMedCrossRefGoogle Scholar
  118. Sousa, M. M., Yan, S. D., Stern, D., and Saraiva, M. J. (2000). Interaction of the receptor for advanced glycation end products (RAGE) with transthyretin triggers nuclear transcription factor kB (NF-kB) activation. Lab. Invest. 80:1101–1110.PubMedGoogle Scholar
  119. Sousa, M. M., Cardoso, I., Fernandes, R., Guimaraes, A., and Saraiva, M. J. (2001). Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates. Am. J. Pathol. 159:1993–2000.PubMedGoogle Scholar
  120. Sousa, M. M. and Saraiva, M. J. (2001). Internalization of transthyretin. Evidence of a novel yet unidentified receptor-associated protein (RAP)-sensitive receptor. J. Biol. Chem. 276:14420–14425.PubMedGoogle Scholar
  121. Sousa, M. M., Fernandes, R., Palha, J., Taboada, A., Vieira, P., and Saraiva, M. (2002). Evidence for early cytotoxicity aggregates in transgenic mice for human transthyretin Leu55Pro. Am. J. Pathol. 161:1935–1948.PubMedGoogle Scholar
  122. Svendsen, I. H., Steensgaard-Hansen, F., and Nordvag, B. Y. (1998). A clinical, echocardiographic and genetic characterization of a Danish kindred with familial amyloid transthyretin methionine 111 linked cardiomyopathy. Eur. Heart J. 19:782–789.PubMedCrossRefGoogle Scholar
  123. Tagoe, C. E., Jacobson, D. R., Gallo, G., and Buxbaum, J. N. (2003). Mice transgenic for human TTR have the same frequency of renal TTR deposition whether maintained in conventional or specific pathogen-free environments. Amyloid J. Protein Folding Disord. 10:262–266.Google Scholar
  124. Tagoe, C. E., French, D., Gallo, G., and Buxbaum, J. N. (2004). Amyloidogenesis is neither accelerated nor enhanced by injections of preformed fibrils in mice transgenic for wild-type human transthyretin: the question of infectivity. Amyloid 11:21–26.PubMedGoogle Scholar
  125. Tajiri, T., Ando, Y., Hata, K., Kamide, K., Hashimoto, M., Nakamura, M., Terazaki, H., Yamashita, T., Kai, H., Haraoka, K., Imasato, A., Takechi, K., Nakagawa, K., Okabe, H., and Ishizaki, T. (2002). Amyloid formation in rat transthyretin: effect of oxidative stress. Clin. Chim. Acta. 323:129–137.PubMedCrossRefGoogle Scholar
  126. Takaoka, Y., Ohta, M., Miyakawa, K., Nakamura, O., Suzuki, M., Takahashi, K., Yamamura, K., and Sakaki, Y. (2004). Cysteine 10 is a key residue in amyloidogenesis of human transthyretin Val30Met. Am. J. Pathol. 164:337–345.PubMedGoogle Scholar
  127. Teng, M. H., Yin, J. Y., Vidal, R., Ghiso, J., Kumar, A., Rabenou, R., Shah, A., Jacobson, D. R., Tagoe, C., Gallo, G., and Buxbaum, J. (2001). Amyloid and nonfibrillar deposits in mice transgenic for wild-type human transthyretin: a possible model for senile systemic amyloidosis. Lab. Invest. 81:385–396.PubMedGoogle Scholar
  128. Tsuzuki, T., Mita, S., Maeda, S., Araki, S., and Shimada, K. (1985). Structure of the human prealbumin gene. J. Biol. Chem. 260:12224–12227.PubMedGoogle Scholar
  129. Van Jaarsveld, P., Branch, W. T., and Robbins, J. (1973). Polymorphism of Rhesus monkey serum prealbumin. J. Biol. Chem. 248:7898–7903.PubMedGoogle Scholar
  130. Vieira, A. V., Sanders, E. J., and Schneider, W. J. (1995). Transport of serum transthyretin into chicken oocytes. J. Biol. Chem. 270:2952–2956.PubMedCrossRefGoogle Scholar
  131. Ward, W. F. (2002). Protein degradation in the aging organism. Prog. Mol. Subcell. Biol. 29:35–42.PubMedGoogle Scholar
  132. Wei, L. (2004). Deposition of transthyretin amyloid is not accelerated by the same amyloid in vivo. Amyloid 11:113–120.PubMedGoogle Scholar
  133. Weizmann Institute of Science/GeneCards, Rehovot (December 31, 2004). Available at Scholar
  134. Westermark, P., Pitkänen, P., Benson, L., Vahlquist, A., Olofsson, B. O., and Cornwell, G. G., III (1985). Serum prealbumin and retinol-binding protein in the prealbumin-related senile and familial forms of systemic amyloidosis. Lab. Invest. 52:314–318.PubMedGoogle Scholar
  135. Westermark, P., Sletten, K., Johansson, B., and Cornwell, G. G., III (1990). Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc. Natl. Acad. Sci. USA 87:2843–2845.PubMedCrossRefGoogle Scholar
  136. White, J. T. and Kelly, J. W. (2001). Support for the multigenic hypothesis of amyloidosis: the binding stoichiometry of retinol-binding protein, vitamin A, and thyroid hormone influences transthyretin amyloidogenicity in vitro. Proc. Natl. Acad. Sci. USA 98:13019–13024.PubMedCrossRefGoogle Scholar
  137. Whitehead, A. S., Skinner, M., Bruns, G. A. P., Costello, W., Edge, M. D., Cohen, A. S., and Sipe, J. D. (1984). Cloning of human prealbumin complementary DNA. Localization of the gene to chromosome 18 and detection of a variant prealbumin allele in a family with familial amyloid polyneuropathy. Mol. Biol. Med. 2:411–423.PubMedGoogle Scholar
  138. Wilce, J. A., Daly, N. L., and Craik, D. J. (2002). Synthesis and structural analysis of the N-terminal domain of the thyroid hormone-binding protein transthyretin. Clin. Chem. Lab. Med. 40:1221–1228.PubMedCrossRefGoogle Scholar
  139. Wojtczak, A. (1996). Structures of human transthyretin complexed with thyroxine at 2.0 A resolution and 3′,5′-dinitro-Nacetyl-L-thyronine at 2.2 A resolution. Acta Crystallogr. D Biol. Crystallogr. 52:758–765.PubMedCrossRefGoogle Scholar
  140. Yan, C., Costa, R. H., Darnell, J. E., Jr., Chen, J. D., and Van Dyke, T. A. (1990). Distinct positive and negative elements control the limited hepatocyte and choroid plexus expression of transthyretin in transgenic mice. EMBO J. 9:869–878.PubMedGoogle Scholar
  141. Yazaki, M., Connors, L. H., Eagle, R. C., Jr., Leff, S. R., Skinner, M., and Benson, M. D. (2002). Transthyretin amyloidosis associated with a novel variant (Trp41Leu) presenting with vitreous opacities. Amyloid 9:263–267.PubMedGoogle Scholar
  142. Yi, S., Takahashi, K., Naito, M., Tashiro, F., Wakasugi, S., Maeda, S., Shimada, K., Yamamura, K., and Araki, S. (1991). Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene: Pathologic similarity to human familial amyloidotic polyneuropathy, type I. Am. J. Pathol. 138:403–412.PubMedGoogle Scholar
  143. Yoshioka, K., Furuya, H., Sasaki, H., Saraiva, M. J. M., Costa, P. P., and Sakaki, Y. (1989). Haplotype analysis of familial amyloidotic polyneuropathy. Evidence for multiple origins of the Val-Met mutation most common to the disease. Hum. Genet. 82:9–13.PubMedCrossRefGoogle Scholar
  144. Zeldenrust, S. R., Skinner, M., Skare, J., and Benson, M. D. (1994). A new transthyretin variant (His 69) associated with vitreous amyloid in an FAP family. Amyloid Int. J. Exp. Clin. Invest. 1:17–22.Google Scholar
  145. Zhang, Q. and Kelly, J. W. (2003). Cys10 mixed disulfides make transthyretin more amyloidogenic under mildly acidic conditions. Biochemistry 42:8756–8761.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Joel N. Buxbaum
    • 1
  1. 1.Division of Research Rheumatology Department of Molecular and Experimental MedicineThe Scripps Research InstituteLa JollaUSA

Personalised recommendations