Skip to main content

Three German fibrinogen Aα-chain amyloidosis patients with the p.Glu526Val mutation


Plasma protein fibrinogen variants cause fibrinogen Aα-chain (AFib) amyloidosis, which presents with hypertension, proteinuria, and azotemia. Six AFib mutations have been reported thus far. We identified three patients who presented with marked proteinuria and serum creatinine elevations. Their kidney biopsies revealed destruction of the glomerular architecture by amyloid deposits with typical, apple-green birefringence in polarized light after Congo red staining. We found immunoreactivity against fibrinogen, which is typical for this type of amyloidosis. We sequenced the FGA exon 5 and demonstrated heterozygosity for the p.Glu526Val mutation in all three cases. This amino acid substitution is the most common fibrinogen Aα-chain variant causing AFib amyloidosis. The mutation has been reported in individuals of European and American descent but not yet in German patients. AFib amyloidosis should therefore be considered an important differential diagnosis in German patients with renal amyloidosis. In the cases described here, the use of antibodies directed against fibrinogen, followed by direct gene sequencing, revealed the underlying cause.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2



fibrinogen Aα-chain gene


hereditary renal amyloidosis




fibrinogen Aα-chain




apolipoprotein AI


apolipoprotein AII


  1. Alexander F, Atkins EL (1975) Familial renal amyloidosis. Case reports, literature review and classification. Am J Med 59:121–128

    Article  PubMed  CAS  Google Scholar 

  2. Benson MD (2005) Ostertag revisited: the inherited systemic amyloidoses without neuropathy. Amyloid 12:75–87

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  4. Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R (1993) Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet 3:252–255

    Article  PubMed  CAS  Google Scholar 

  5. Bohne S, Sletten K, Menard R, Buhling F, Vockler S, Wrenger E, Roessner A, Rocken C (2004) Cleavage of AL amyloid proteins and AL amyloid deposits by cathepsins B, K, and L. J Pathol 203:528–537

    Article  PubMed  CAS  Google Scholar 

  6. Bybee, A., Hollenbeck, M., Debusman, E., Gopaul, D., Gilbertson, J., and Lachmann, H. J. (2004) Hereditary renal amyloidosis in a German family associated with fibrinogen Aalhpa chain Glu540Val. In: Xth International Symposium on Amyloid and Amyloidosis, Tours, Loire Valley, France,71.

  7. de Carvalho M, Linke RP, Domingos F, Evangelista T, Ducla-Soares JL, Nathrath WB, zevedo-Coutinho C, Lima R, Saraiva MJ (2004) Mutant fibrinogen A-alpha-chain associated with hereditary renal amyloidosis and peripheral neuropathy. Amyloid 11:200–207

    Article  PubMed  CAS  Google Scholar 

  8. Doolittle RF, Watt KW, Cottrell BA, Strong DD, Riley M (1979) The amino acid sequence of the alpha-chain of human fibrinogen. Nature 280:464–468

    Article  PubMed  CAS  Google Scholar 

  9. Gregorini G, Izzi C, Obici L, Tardanico R, Rocken C, Viola BF, Capistrano M, Donadei S, Biasi L, Scalvini T, Merlini G, Scolari F (2005) Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis. J Am Soc Nephrol 16:3680–3686

    Article  PubMed  CAS  Google Scholar 

  10. Hamidi AL, Liepnieks JJ, Uemichi T, Rebibou JM, Justrabo E, Droz D, Mousson C, Chalopin JM, Benson MD, Delpech M, Grateau G (1997) Renal amyloidosis with a frame shift mutation in fibrinogen a alpha-chain gene producing a novel amyloid protein. Blood 90:4799–4805

    Google Scholar 

  11. Hamidi AL, Fournier V, Billerey C, Justrabo E, Chevet D, Droz D, Pecheux C, Delpech M, Grateau G (1998) Fibrinogen A alpha chain mutation (Arg554 Leu) associated with hereditary renal amyloidosis in a French family. Amyloid 5:279–284

    Google Scholar 

  12. Hawkins PN (2003) Hereditary systemic amyloidosis with renal involvement. J Nephrol 16:443–448

    PubMed  CAS  Google Scholar 

  13. Kang HG, Bybee A, Ha IS, Park MS, Gilbertson JA, Cheong HI, Choi Y, Hawkins PN (2005) Hereditary amyloidosis in early childhood associated with a novel insertion–deletion (indel) in the fibrinogen A alpha chain gene. Kidney Int 68:1994–1998

    Article  PubMed  CAS  Google Scholar 

  14. Lachmann HJ, Booth DR, Booth SE, Bybee A, Gilbertson JA, Gillmore JD, Pepys MB, Hawkins PN (2002) Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. N Engl J Med 346:1786–1791

    Article  PubMed  CAS  Google Scholar 

  15. Mousson C, Heyd B, Justrabo E, Rebibou JM, Tanter Y, Miguet JP, Rifle G (2006) Successful hepatorenal transplantation in hereditary amyloidosis caused by a frame-shift mutation in fibrinogen A alpha-chain gene. Am J Transplant 6:632–635

    Article  PubMed  CAS  Google Scholar 

  16. Neerman-Arbez M (2006) Molecular basis of fibrinogen deficiency. Pathophysiol Haemost Thromb 35:187–198

    Article  PubMed  Google Scholar 

  17. Nichols WC, Dwulet FE, Liepnieks J, Benson MD (1988) Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem Biophys Res Commun 156:762–768

    Article  PubMed  CAS  Google Scholar 

  18. Ostertag B (1950) Familiere amyloid-erkrankung. Zeitschrift für Menschliches Vererbungs und Konstitutionslehre 30:105–115

    Google Scholar 

  19. Serpell LC, Benson M, Liepnieks JJ, Fraser PE (2007) Structural analyses of fibrinogen amyloid fibrils. Amyloid 14:199–203

    Article  PubMed  CAS  Google Scholar 

  20. Uemichi T, Liepnieks JJ, Benson MD (1994) Hereditary renal amyloidosis with a novel variant fibrinogen. J Clin Invest 93:731–736

    Article  PubMed  CAS  Google Scholar 

  21. Uemichi T, Liepnieks JJ, Alexander F, Benson MD (1996) The molecular basis of renal amyloidosis in Irish–American and Polish–Canadian kindreds. QJM 89:745–750

    Article  PubMed  CAS  Google Scholar 

  22. Uemichi T, Liepnieks JJ, Yamada T, Gertz MA, Bang N, Benson MD (1996) A frame shift mutation in the fibrinogen A alpha chain gene in a kindred with renal amyloidosis. Blood 87:4197–4203

    PubMed  CAS  Google Scholar 

  23. Uemichi T, Liepnieks JJ, Gertz MA, Benson MD (1998) Fibrinogen A alpha chain Leu 554: an African–American kindred with late onset renal amyloidosis. Amyloid 5:188–192

    PubMed  CAS  Google Scholar 

  24. Zeldenrust S, Gertz M, Uemichi T, Bjornsson J, Wiesner R, Schwab T, Benson M (2003) Orthotopic liver transplantation for hereditary fibrinogen amyloidosis. Transplantation 75:560–561

    Article  PubMed  CAS  Google Scholar 

Download references


This project was supported by grants of the European Union (EU FP6 EURAMY). We wish to thank Dr. August (Münster), Prof. Krenn (Trier) and Prof. Waldherr (Heidelberg) for kindly providing the kidney biopsies for immunohistochemical analyses, Dr. Thomas Ackermann (Mechernich) and Dr. Kerstin Traser (Halle/Saale) for admission of the patients and Prof. Luft (Berlin) for his critical revision of the manuscript.

Conflict of interest statement

We declare that we have no conflict of interest.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Christoph Röcken.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Eriksson, M., Schönland, S., Bergner, R. et al. Three German fibrinogen Aα-chain amyloidosis patients with the p.Glu526Val mutation. Virchows Arch 453, 25–31 (2008).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: