Skip to main content
SpringerLink
Log in

Genetics: Clinical Implications of Transthyretin Amyloidosis

  • Chapter
  • First Online:
Recent Advances in Transthyretin Evolution, Structure and Biological Functions

Abstract

Transthyretin (TTR) is a fascinating protein. Its transport properties for thyroxin and Vitamin A, its classic β-barrel structure, stable homo-tetrameric structure in solution and its phylogenetic evolution have all been of great interest to scientific study. Even the lack of pathology in its absence, in TTR gene knockout mice, has been of great interest. Its entire notoriety in the area of human pathology, however, is that it readily forms amyloid fibrils, usually due to single amino acid mutations in its primary structure but in some cases even when there is no gene or amino acid structural alteration. TTR amyloidosis is strictly a human disease and more than 100 TTR mutations having been associated with the disease. A few of the mutations are found in large kindreds worldwide while many mutations have been found in only single individuals or single families. In depth analysis of this autosomal dominant disease with an appreciation of the variations in phenotypes suggests clues which may help rationalize basic physical and chemical studies of TTR with biochemical processes which must be involved in the generation of clinical disease. This chapter discusses the clinical aspects of the disease and tries to use these observations to contemplate the intricacies of pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Andersson R (1970) Hereditary amyloidosis with polyneuropathy. Acta Med Scand 188:85–94.

    Article  Google Scholar 

  • Andersson R, Kassman T (1968) Vitreous opacities in primary familial amyloidosis. Acta Ophthal (Copenh) 46:441–447.

    Article  CAS  Google Scholar 

  • Andrade C (1952) A peculiar form of peripheral neuropathy. Familial atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75:408–427.

    Article  CAS  PubMed  Google Scholar 

  • Araki S, Mawatari S, Ohta M, Nakajima A, Kuroiwa Y (1968) Polyneuritic amyloidosis in Japanese family. Arch Neurol 18:593–602.

    CAS  PubMed  Google Scholar 

  • Baures PW, Oza VB, Peterson SA, Kelly JW (1999) Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, Flufenamic Acid. Bioorganic Med Chem 7:1339–1347.

    Article  CAS  Google Scholar 

  • Benson MD (2003) The hereditary amyloidoses. In: Elsevier UK (ed) Best Practice and Research Clinical Rheumatology, chap 2, vol 17, pp 909−927.

    Google Scholar 

  • Benson MD, Kluve-Beckerman B, Zeldenrust SR, Siesky AM, Bodenmiller DM, Showalter AD, Sloop KW (2006) Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve 33:609–618.

    Article  CAS  PubMed  Google Scholar 

  • Benson MD, Kluve-Beckerman BB, Liepnieks JJ, Murrell JR, Hanes D, Uemichi T (1996) Metabolism of amyloid proteins. In. Bock GR, Goode JA (eds) The Nature and Origin of Amyloid Fibrils, Ciba Foundation Symposium 199. Wiley, New York, pp. 104–118.

    Google Scholar 

  • Benson MD, Cohen AS (1977) Generalized amyloid in a family of Swedish origin. A study of 426 family members in 7 generations of a new kinship with neuropathy, nephropathy and central nervous system involvement. Ann Intern Med 86:419–424.

    CAS  PubMed  Google Scholar 

  • Benson MD, Dwulet FE (1983) Prealbumin and retinol binding protein serum concentrations in the Indiana type hereditary amyloidosis. Arthritis Rheum 26:1493–1498.

    Article  CAS  PubMed  Google Scholar 

  • Benson MD, Kincaid JC (2007) The molecular biology and clinical features of amyloid neuropathy. Muscle Nerve 36:411–423.

    Article  CAS  PubMed  Google Scholar 

  • Benson MD, Wallace MR, Tejada E, Bauman H, Page B (1987) Hereditary amyloidosis: description of a new American kindred with late onset cardiomyopathy. Arthritis Rheum 30:195–200.

    Article  CAS  PubMed  Google Scholar 

  • Block WD, Jackson CE, Falls HF, Carey JH, Curtis AC, Rukavina JG (1956) Primary systemic amyloidosis: A review and an experimental, genetic, and clinical study of 29 cases with particular emphasis on the familial form. Medicine 35:239–334.

    CAS  PubMed  Google Scholar 

  • Connors LH, Lim A, Prokaeva T, Roskens VA, Costello CE (2003) Tabulation of human transthyretin (TTR) variants. Amyloid 10:160–184.

    CAS  PubMed  Google Scholar 

  • Cornwell GG, Westermark P, Natvig JB, Murdoch W (1981) Senile cardiac amyloid: evidence that fibrils contain a protein immunologically related to prealbumin. Immunology 44:447–452.

    CAS  PubMed  Google Scholar 

  • Dowell JD, Fleck JD, Vakili ST, Benson MD (2007) Familial oculoleptomeningeal amyloidosis with primary angiitis of the CNS. Neurology 68:77–78.

    Article  PubMed  Google Scholar 

  • Dubrey SW, Davidoff R, Skinner M, Bergethon P, Lewis D, Falk R (1997) Progression of ventricular wall thickening after liver transplantation for familial amyloidosis. Transplantation 64:74–80.

    Article  CAS  PubMed  Google Scholar 

  • Dwulet FE, Benson MD (1986) Characterization of a transthyretin (prealbumin) variant associated with familial amyloidotic polyneuropathy type II (Indiana/Swiss). J Clin Invest 78:880–886.

    Article  CAS  PubMed  Google Scholar 

  • Falls HF, Jackson JH, Carey JG, Rukavina JG, Block WD (1955) Ocular manifestations of hereditary primary systemic amyloidosis. Arch Ophthalmol 54:660–664.

    CAS  Google Scholar 

  • Goebel HH, Seddigh S, Hopf HC, Uemichi T, Benson MD, McKusick VA (1997) A European family with histidine 58 transthyretin mutation in familial amyloid polyneuropathy. Neuromuscular Disorders 7:229–230.

    Article  CAS  PubMed  Google Scholar 

  • Gorevic PD, Prelli FC, Wright J, Pras M, Frangione B (1989) Systemic senile amyloidosis. Identification of a newprealbumin (transthyretin) variant in cardiac tissue: immunologic and biochemical similarity to one form of familial amyloidotic polyneuropathy. Clin Invest 83: 836–843.

    CAS  Google Scholar 

  • Goren H, Steinberg MC, Farboody GH (1980) Familial oculoleptomeningeal amyloidosis. Brain 103:473–495.

    Article  CAS  PubMed  Google Scholar 

  • Gustavsson Å, Engström U, Westermark P (1994) Mechanisms of transthyretin amyloidogenesis. Antigenic mapping of transthyretin purified from plasma and amyloid fibrils and within in situ tissue localizations. Am J Pathol 144:1301–1311.

    CAS  Google Scholar 

  • Hamilton JA, Benson MD (2001) Transthyretin: A review from a structural perspective. Cell Mol Life Sci 58:1491–1521.

    Article  CAS  PubMed  Google Scholar 

  • Hammarström P, Wiseman RL, Powers ET, Kelly JW (2003) Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299:713–716.

    Article  PubMed  Google Scholar 

  • Harats N, Worth R, Benson MD (1989) Spinal claudication in systemic amyloidosis. J Rheum 16:1003–1006.

    CAS  PubMed  Google Scholar 

  • Holmgren G, Haettner E, Nordenson I, Sandgren O, Steen L, Lundgren E (1988) Homozygosity for the transthyretin-Met30-gene in two Swedish sibs with familial amyloidotic polyneuropathy. Clin Genet 34:333–338.

    Article  CAS  PubMed  Google Scholar 

  • Holmgren G, Holmberg E, Lindstrom A, Lindstrom E, Nordenson I, Sandgren O, Steen L, Svensson B, Lndgren E, von Gabain A (1988) Diagnosis of familial amyloidotic polyneuropathy in Sweden by RFLP analysis. Clin Genet 33:176–180.

    Article  CAS  PubMed  Google Scholar 

  • Holmgren G, Steen L, Ekstedt J, Groth CG, Ericzon BG, Eriksson S, Andersen O, Karlberg I, Norden G, Nakazato M, Hawkins P, Richardson S, Pepys M (1991) Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 40:242–246.

    Article  CAS  PubMed  Google Scholar 

  • Jacobson DR, Pastore RD, Yaghoubian R, Kane I, Gallo G, Buck FS, Buxbaum JN (1997) Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med 336:466–473.

    Article  CAS  PubMed  Google Scholar 

  • Kincaid JC, Wallace RW, Benson MD (1989) Late onset familial amyloid polyneuropathy in an American family of English origin. Neurology 39:861–863.

    CAS  PubMed  Google Scholar 

  • Lessell S, Wolf PA, Benson MD, Cohen AS (1975) Scalloped pupils in familial amyloidosis. N Engl J Med 293:914–915.

    Article  CAS  PubMed  Google Scholar 

  • Libbey CA, Rubinow A, Shirahama T, Deal C, Cohen AS (1984) Familial amyloid polyneuropathy. Demonstration of prealbumin in a kinship of German/English ancestry with onset in the seventh decade. Am J Med 76:18–24.

    CAS  Google Scholar 

  • Liepnieks JJ, Benson MD (2007) Progression of cardiac amyloid deposition in hereditary transthyretin amyloidosis patients after liver transplantation. Amyloid 14:277–282.

    Article  CAS  PubMed  Google Scholar 

  • Liepnieks JJ, Wilson DL, Benson MD (2006) Biochemical characterization of vitreous and cardiac amyloid in Ile84Ser transthyretin amyloidosis. Amyloid 13:170–177.

    Article  CAS  PubMed  Google Scholar 

  • Mahloudji M, Teasdall RD, Adamkiewicz JJ, Hartmann WH, Lambird PA, McKusick VA (1969) The genetic amyloidoses. With particular reference to hereditary neuropathic amyloidosis, type II (Indiana or Rukavina type). Medicine 48:1–37.

    Article  CAS  PubMed  Google Scholar 

  • Murakami T, Maeda S, Yi S, Ikegawa S, Kawashima E, Onodera S, Shimada K, Araki S (1992) A novel transthyretin mutation associated with familial amyloidotic polyneuropoathy. Biochem Biophys Res Commun 182:520–526.

    Article  CAS  PubMed  Google Scholar 

  • Nichols WC, Liepnieks JJ, McKusick VA, Benson MD (1989) Direct sequencing of the gene for Maryland/German familial amyloidotic polyneuropathy type II and genotyping by allele-specific enzymatic amplification. Genomics 5:535–540.

    Article  CAS  PubMed  Google Scholar 

  • Nichols WC, Liepnieks JJ, Snyder EL, Benson MD (1991). Senile cardiac amyloidosis associated with homozygosity for a transthyretin variant (Ile-122). J Lab Clin Med 117:175–180.

    CAS  PubMed  Google Scholar 

  • Petersen RB, Goren H, Cohen M, Richardson SL, Tresser N, Lynn A, Gali M, Estes M, Gambetti P. (1997) Transthyretin amyloidosis: a new mutation associated with dementia. Ann Neurol 41: 307–313.

    Article  CAS  PubMed  Google Scholar 

  • Peterson SA, Klabunde T, Lashuel HA, Purkey H, Sacchettini JC, Kelly JW (1998) Inhibiting transthyretin conformational changes that lead to amyloid fibril formation. Proc Natl Acad Sci USA 95:12957–12960.

    Google Scholar 

  • Pitkänen P, Westermark P, Cornwell GG (1984) Senile systemic amyloidosis. Am J Pathol 117: 391–399.

    PubMed  Google Scholar 

  • Pollak A, Falk RH (1993) Left ventricular systeolic dysfunction precipitated by verapamil in cardiac amyloidosis. Chest 104:618–620.

    Article  CAS  PubMed  Google Scholar 

  • Rosen HN, Moses AC, Murrell JR, Liepnieks JJ, Holmgren G, Sandgren O, Steen L, Benson MD (1993) Thyroxine interactions with transthyretin: a comparison of 10 different naturally-occurring transthyretin variants. J Clin Endo Metab 77:370–374

    Article  CAS  Google Scholar 

  • Rukavina JG, Block WD, Jackson CE, Falls HF, Carey JH, Curtis AC (1956) Primary systemic amyloidosis: a review and an experimental, genetic, and clinical study of 29 cases with particular emphasis on the familial form. Medicine 35:239–334.

    Article  PubMed  Google Scholar 

  • Saunders AM, Schmader K, Breitner JC, Benson MD, Brown WT, Goldfard L, Goldgaber D, Manwaring MG, Szymanski MH, McCrown N, Dole KC, Schmechel DE, Strittmatter WJ, Pericak-Vance MA, Roses AD (1993) Apolipoprotein E 4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases. Lancet 342:710–711.

    Article  CAS  PubMed  Google Scholar 

  • Sandgren O (1995) Ocular amyloidosis, with special reference to the hereditary forms with vitreous involvement. Surv Ophthalmol 40:173–196.

    Article  CAS  PubMed  Google Scholar 

  • Satier F, Nichols WC, Benson MD (1990) Diagnosis of familial amyloidotic polyneuropathy in France. Clin Genet 38:469–473.

    Article  CAS  PubMed  Google Scholar 

  • Sequeiros J, Saraiva MJ (1987) Onset in the seventh decade and lack of symptoms in heterozygotes for the TTRMet30 mutation in hereditary amyloid neuropathy − type I (Portuguese, Andrade). Am J Med Genet 27:345–357.

    Article  CAS  PubMed  Google Scholar 

  • Shur O, Danielsson A, Holmgren G, Steen L (1994) Malnutrition and gastrointestinal dysfunction as prognostic factors for survival in familial amyloidotic polyneuropathy. J Int Med 479-485.

    Google Scholar 

  • Skinner M, Connors LH, Rubinow A, Libbey C, Sipe JD, Cohen AS (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.

    Article  CAS  PubMed  Google Scholar 

  • Ueno S, Uemichi T, Yorifuji S, Tarui S (1990) A novel variant of transthyretin (Tyr114 to Cys) deduced from the nucleotide sequences of gene fragments from familial amyloidotic polyneuropathy in Japanese sibling cases. Biochem Biophys Res Commun 169:143–147.

    Article  CAS  PubMed  Google Scholar 

  • Vahlquist A, Peterson PA, Wibell L (1973) Metabolism of the vitamin A transporting protein complex. 1. Turnover studies in normal persons and in patients with chronic renal failure. Eur J Clin Invest 3:352–362.

    CAS  Google Scholar 

  • Waits RP, Yamada T, Uemichi T, Benson MD (1995) Low plasma concentrations of retinol-binding protein in individuals with mutations affecting position 84 of the transthyretin molecule. Clin Chem 41:1288–1291.

    CAS  PubMed  Google Scholar 

  • Wallace MR, Dwulet FE, Conneally PM, Benson MD (1986) Biochemical and molecular genetic characteristic of a new variant prealbumin associated with hereditary amyloidosis. J Clin Invest 78:6–12.

    Article  CAS  PubMed  Google Scholar 

  • Wallace MR, Dwulet FE, Williams EC, Conneally PM, Benson MD (1988) Identification of a new hereditary amyloidosis prealbumin variant, tyr77, and detection of the gene by DNA analysis. J Clin Invest 81:189–193.

    Article  CAS  PubMed  Google Scholar 

  • Westermark P, Pitkanen P, Benson L, Vahlquist A, Olofsson BO, Cornwell GG III (1985) Serum prealbumin and retinol-binding protein in the prealbumin-related senile and familial forms of systemic amyloidosis. Lab Invest 52:314–318.

    CAS  PubMed  Google Scholar 

  • Westermark P, Sletten K, Johansson B, Cornwell GG (1990) Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci USA 87:2843–2845.

    Article  CAS  PubMed  Google Scholar 

  • Yamashita T, Hamidi Asl K, Yazaki M, Benson MD (2005) A prospective evaluation of the transthyretin Ile122 allele frequency in an African-American population. Amyloid J Protein Folding Disord 12:127–130.

    Article  CAS  Google Scholar 

  • Yazaki M, Connors LH, Eagle Jr, RC, Leff SR, Skinner M, Benson MD (2002) Transthyretin amyloidosis associated with a novel variant (Trp41Leu) presenting with vitreous opacities. Amyloid J Protein Folding Disord 9:263–267.

    Google Scholar 

  • Yazaki M, Yamashita T, Kincaid J, Scott J, Auger R, Dyck P, Benson MD (2002) Rapidly progressive amyloid polyneuropathy associated with a novel variant transthyretin Ser 25. Muscle Nerve 25:244–250.

    Article  CAS  PubMed  Google Scholar 

  • Yoshioka K, Furuya H, Sasaki H, Saraiva MJM, Costa PP, Sakaki Y (1980) Haplotype analysis of familial amyloidotic polyneuropathy. Hum Genet 82:9–13.

    Article  Google Scholar 

  • Zhao N, Aoyama N, Benson MD, Skinner M, Satier F, Sakaki Y (1994) Haplotype analysis of His58, Ala60 and Tyr77 types of familial amyloidotic polyneuropathy. Amyloid Int J Exp Clin Invest 1:75–79.

    CAS  Google Scholar 

  • Zólyomi Z, Benson MD, Halász K, Uemichi T, Fekete G (1998) Transthyretin mutation (Serine 84) associated with familial amyloid polyneuropathy in a Hungarian family. Amyloid Int J Exp Clin Invest 5:30–34.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Indiana University School of Medicine, 635 Barnhill Drive, MS-128, Indianapolis, IN, 46202-5126, USA

    Merrill D Benson

Authors
  1. Merrill D Benson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Merrill D Benson .

Editor information

Editors and Affiliations

  1. School of Medical Sciences, RMIT University, Bundoora, VIC 3083, Bundoora West Campus, Australia

    Samantha J. Richardson

  2. Medical Research Institute, Hauptman-Woodward, 700 Elliott Street, Buffalo, NY, 14203, USA

    Vivian Cody

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Benson, M.D. (2009). Genetics: Clinical Implications of Transthyretin Amyloidosis. In: Richardson, S.J., Cody, V. (eds) Recent Advances in Transthyretin Evolution, Structure and Biological Functions. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00646-3_11

Download citation

Publish with us

Policies and ethics

Search

Navigation