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Logo of jcinvestThe Journal of Clinical Investigation
J Clin Invest. 1994 February; 93(2): 731–736.
PMCID: PMC293912

Hereditary renal amyloidosis with a novel variant fibrinogen.


Two families with hereditary renal amyloidosis were found to have a novel mutation in the fibrinogen A alpha chain gene. This form of amyloidosis is an autosomal dominant condition characterized by proteinuria, hypertension, and subsequent azotemia. DNAs of patients with amyloidosis were screened for a polymorphism in fibrinogen A alpha chain gene by single-strand conformation polymorphism analysis, and affected individuals from two kindreds were found to have a mutation. Both of these kindreds are American of Irish descent presenting with non-neuropathic, nephropathic amyloidosis in the fifth to the seventh decade of life. DNA sequencing showed a point mutation in the fibrinogen A alpha chain gene that is responsible for substitution of valine for glutamic acid at position 526. By restriction fragment length polymorphism analysis, 7 affected individuals and 14 asymptomatic individuals in these two kindreds were positive for the fibrinogen A alpha chain Val 526 gene. Fibrinogen was isolated from plasma of a heterozygous gene carrier and shown to contain approximately 50% variant fibrinogen. Discovery of this new mutation confirms the association between fibrinogen A alpha chain variant and hereditary renal amyloidosis and establishes a new biochemical subtype of amyloidosis.

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Selected References

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  • Benson MD. Inherited amyloidosis. J Med Genet. 1991 Feb;28(2):73–78. [PMC free article] [PubMed]
  • Dwulet FE, Benson MD. Polymorphism of human plasma thyroxine binding prealbumin. Biochem Biophys Res Commun. 1983 Jul 29;114(2):657–662. [PubMed]
  • Tawara S, Nakazato M, Kangawa K, Matsuo H, Araki S. Identification of amyloid prealbumin variant in familial amyloidotic polyneuropathy (Japanese type). Biochem Biophys Res Commun. 1983 Nov 15;116(3):880–888. [PubMed]
  • Nichols WC, Gregg RE, Brewer HB, Jr, Benson MD. A mutation in apolipoprotein A-I in the Iowa type of familial amyloidotic polyneuropathy. Genomics. 1990 Oct;8(2):318–323. [PubMed]
  • Maury CP, Kere J, Tolvanen R, de la Chapelle A. Finnish hereditary amyloidosis is caused by a single nucleotide substitution in the gelsolin gene. FEBS Lett. 1990 Dec 10;276(1-2):75–77. [PubMed]
  • Levy E, Haltia M, Fernandez-Madrid I, Koivunen O, Ghiso J, Prelli F, Frangione B. Mutation in gelsolin gene in Finnish hereditary amyloidosis. J Exp Med. 1990 Dec 1;172(6):1865–1867. [PMC free article] [PubMed]
  • de la Chapelle A, Tolvanen R, Boysen G, Santavy J, Bleeker-Wagemakers L, Maury CP, Kere J. Gelsolin-derived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187. Nat Genet. 1992 Oct;2(2):157–160. [PubMed]
  • Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704–706. [PubMed]
  • Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science. 1991 Oct 4;254(5028):97–99. [PubMed]
  • Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991 Oct 31;353(6347):844–846. [PubMed]
  • Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990 Jun 1;248(4959):1124–1126. [PubMed]
  • Ghiso J, Pons-Estel B, Frangione B. Hereditary cerebral amyloid angiopathy: the amyloid fibrils contain a protein which is a variant of cystatin C, an inhibitor of lysosomal cysteine proteases. Biochem Biophys Res Commun. 1986 Apr 29;136(2):548–554. [PubMed]
  • Benson MD, Liepnieks J, Uemichi T, Wheeler G, Correa R. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet. 1993 Mar;3(3):252–255. [PubMed]
  • Madisen L, Hoar DI, Holroyd CD, Crisp M, Hodes ME. DNA banking: the effects of storage of blood and isolated DNA on the integrity of DNA. Am J Med Genet. 1987 Jun;27(2):379–390. [PubMed]
  • Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. [PubMed]
  • Uemichi T, Murrell JR, Zeldenrust S, Benson MD. A new mutant transthyretin (Arg 10) associated with familial amyloid polyneuropathy. J Med Genet. 1992 Dec;29(12):888–891. [PMC free article] [PubMed]
  • Chung DW, Harris JE, Davie EW. Nucleotide sequences of the three genes coding for human fibrinogen. Adv Exp Med Biol. 1990;281:39–48. [PubMed]
  • Nichols WC, Liepnieks JJ, McKusick VA, Benson MD. Direct sequencing of the gene for Maryland/German familial amyloidotic polyneuropathy type II and genotyping by allele-specific enzymatic amplification. Genomics. 1989 Oct;5(3):535–540. [PubMed]
  • CLAUSS A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol. 1957 Apr;17(4):237–246. [PubMed]
  • Mancini G, Carbonara AO, Heremans JF. Immunochemical quantitation of antigens by single radial immunodiffusion. Immunochemistry. 1965 Sep;2(3):235–254. [PubMed]
  • Deutsch DG, Mertz ET. Plasminogen: purification from human plasma by affinity chromatography. Science. 1970 Dec 4;170(3962):1095–1096. [PubMed]
  • Engvall E, Ruoslahti E. Binding of soluble form of fibroblast surface protein, fibronectin, to collagen. Int J Cancer. 1977 Jul 15;20(1):1–5. [PubMed]
  • Liepnieks JJ, Dwulet FE, Benson MD. Amino acid sequence of a kappa I primary (AL) amyloid protein (AND). Mol Immunol. 1990 Jun;27(6):481–485. [PubMed]
  • Doolittle RF, Watt KW, Cottrell BA, Strong DD, Riley M. The amino acid sequence of the alpha-chain of human fibrinogen. Nature. 1979 Aug 9;280(5722):464–468. [PubMed]
  • Koopman J, Haverkate F, Grimbergen J, Egbring R, Lord ST. Fibrinogen Marburg: a homozygous case of dysfibrinogenemia, lacking amino acids A alpha 461-610 (Lys 461 AAA-->stop TAA). Blood. 1992 Oct 15;80(8):1972–1979. [PubMed]
  • Siebenlist KR, Mosesson MW, DiOrio JP, Soria J, Soria C, Caen JP. The polymerization of fibrinogen Dusart (A alpha 554 Arg-->Cys) after removal of carboxy terminal regions of the A alpha-chains. Blood Coagul Fibrinolysis. 1993 Feb;4(1):61–65. [PubMed]
  • Koopman J, Haverkate F, Grimbergen J, Lord ST, Mosesson MW, DiOrio JP, Siebenlist KS, Legrand C, Soria J, Soria C, et al. Molecular basis for fibrinogen Dusart (A alpha 554 Arg-->Cys) and its association with abnormal fibrin polymerization and thrombophilia. J Clin Invest. 1993 Apr;91(4):1637–1643. [PMC free article] [PubMed]
  • Dwulet FE, Benson MD. Primary structure of an amyloid prealbumin and its plasma precursor in a heredofamilial polyneuropathy of Swedish origin. Proc Natl Acad Sci U S A. 1984 Feb;81(3):694–698. [PubMed]
  • Dwulet FE, Benson MD. Characterization of a transthyretin (prealbumin) variant associated with familial amyloidotic polyneuropathy type II (Indiana/Swiss). J Clin Invest. 1986 Oct;78(4):880–886. [PMC free article] [PubMed]
  • Weiss SW, Page DL. Amyloid nephropathy of Ostertag with special reference to renal glomerular giant cells. Am J Pathol. 1973 Sep;72(3):447–460. [PubMed]
  • Weiss SH, Page DL. Amyloid nephropathy of Ostertag: report of a kindred. Birth Defects Orig Artic Ser. 1974;10(4):67–68. [PubMed]
  • Alexander F, Atkins EL. Familial renal amyloidosis. Case reports, literature review and classification. Am J Med. 1975 Jul;59(1):121–128. [PubMed]
  • Mornaghi R, Rubinstein P, Franklin EC. Studies on the pathogenesis of a familial form of renal amyloidosis. Trans Assoc Am Physicians. 1981;94:211–216. [PubMed]
  • Mornaghi R, Rubinstein P, Franklin EC. Familial renal amyloidosis: case reports and genetic studies. Am J Med. 1982 Oct;73(4):609–614. [PubMed]
  • Lanham JG, Meltzer ML, De Beer FC, Hughes GR, Pepys MB. Familial amyloidosis of Ostertag. Q J Med. 1982;51(201):25–32. [PubMed]
  • Pepys MB, Hawkins PN, Booth DR, Vigushin DM, Tennent GA, Soutar AK, Totty N, Nguyen O, Blake CC, Terry CJ, et al. Human lysozyme gene mutations cause hereditary systemic amyloidosis. Nature. 1993 Apr 8;362(6420):553–557. [PubMed]
  • Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 50-1987. A 43-year-old woman with hepatic failure after renal transplantation because of amyloidosis. N Engl J Med. 1987 Dec 10;317(24):1520–1531. [PubMed]
  • Zalin AM, Jones S, Fitch NJ, Ramsden DB. Familial nephropathic non-neuropathic amyloidosis: clinical features, immunohistochemistry and chemistry. Q J Med. 1991 Nov;81(295):945–956. [PubMed]
  • Soutar AK, Hawkins PN, Vigushin DM, Tennent GA, Booth SE, Hutton T, Nguyen O, Totty NF, Feest TG, Hsuan JJ, et al. Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7389–7393. [PubMed]

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