Original article| Volume 102, ISSUE 4, P590-603, October 1983

Studies on plasma transthyretin (prealbumin) in familial amyloidotic polyneuropathy, Portuguese type

  • Maria João Mascarenhas Saraiva
    From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, N. Y., USA

    From the Centro de Estudos de Paramiloidose, Hospital de St. Antonio, Porto, Portugal
    Search for articles by this author
  • Pedro P. Costa
    From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, N. Y., USA

    From the Centro de Estudos de Paramiloidose, Hospital de St. Antonio, Porto, Portugal
    Search for articles by this author
  • DeWitt S. Goodman
    Reprint requests: Dr. DeWitt S. Goodman, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th St., New York, N. Y. 10032.
    From the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, N. Y., USA

    From the Centro de Estudos de Paramiloidose, Hospital de St. Antonio, Porto, Portugal
    Search for articles by this author
  • Author Footnotes
    1 Dr. Saraiva was a recipient of a scholarship from Instituto Nacional de Investigacao Ciêntifíca during part of this work.
      This paper is only available as a PDF. To read, Please Download here.


      Amyloid deposits in several heredofamilial forms of amyloidosis are known to be chemically related to transthyretin (TTR, the plasma protein usually referred to as prealbumin). A genetic mutation, leading to an abnormal TTR, may be involved. Studies were conducted to investigate whether or not Portuguese patients with familial amyloidotic polyneuropathy (FAP) have an abnormal species of TTR circulating in their plasma and, if so, whether this might have any impact on vitamin A transport and retinol-binding protein (RBP) metabolism in these patients. The initial studies examined the plasma concentrations of TTR, RBP, and retinol in patients with FAP. Significantly reduced (p < 0.005) levels of TTR were found in patients with FAP. The TTR levels in 24 FAP patients were approximately two thirds of those of a group of 18 control subjects from the same geographic area. In contrast, RBP levels were not reduced, nor was there an abnormality in the ratio of retinol to RBP, in the patients with FAP. Thus there does not appear to be an abnormality in vitamin A transport in Portuguese patients with FAP. There does, however, appear to be an abnormality of TTR metabolism, accounting for the reduced plasma levels of TTR. TTR was isolated from pooled sera of the FAP patients and was characterized in detail. FAP-TTR was indistinguishable from normal TTR with regard to a variety of parameters, including (1) electrophoretic mobility, (2) chromatographic behavior, (3) molecular weight, (4) stability of the TTR tetramer, (5) immunoreactivity in TTR radioimmunoassays using antisera prepared against both normal and FAP-TTR, (6) ability to form a protein-protein complex with RBP and affinity for RBP as assessed by polarization of fluorescence, and (7) overall amino acid composition. The possible explanations are as follows: (1) an abnormal TTR molecule is not produced in this form of FAP; (2) the abnormal molecule is present in only trace amounts (not detectable in the present study) in FAP plasma; or (3) the abnormal TTR is structurally almost identical to normal TTR and does not differ from normal TTR with regard to the various physical and chemical properties investigated in this study. Preliminary observations suggest that FAP patients do produce an abnormal form of TTR that selectively deposits in tissues as amyloid protein.


      transthyretin ((TTR)), retinol-binding protein ((RBP)), familial amyloidotic polyneuropathy ((FAP)), normal TTR ((N-TTR)), TTR from patients with FAP ((FAP-TTR)), sodium dodecyl sulfate ((SDS)), polyacrylamide gel electrophoresis ((PAGE)), blood urea nitrogen ((BUN)), diethylaminoethyl ((DEAE))
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Translational Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kanda Y
        • Goodman DS
        • Canfield RE
        • Morgan FJ
        The amino acid sequence of human plasma prealbumin.
        J Biol Chem. 1974; 249: 6796
        • Blake CCF
        • Geisow MJ
        • Swan IDA
        • Rerat C
        • Rerat B
        Structure of human plasma prealbumin at 2.5 Å resolution. A preliminary report on the polypeptide chain conformation, quaternary structure and thyroxine binding.
        J Mol Biol. 1974; 88: 1
        • Blake CCF
        • Geisow JJ
        • Oatley SJ
        • Rérat B
        • Rérat C
        Structure of prealbumin. Secondary, tertiary, and quaternary interactions determined by Fourier refinement at 1.8 Å.
        J Mol Biol. 1978; 121: 339
        • Ferguson RN
        • Edelhoch H
        • Saroff HA
        • Robbins J
        Negative cooperativity in the binding of thyroxine to human serum prealbumin.
        Biochemistry. 1975; 14: 282
        • van Jaarsveld PP
        • Edelhoch H
        • Goodman DS
        • Robbins J
        The interaction of human plasma retinol-binding protein with prealbumin.
        J Biol Chem. 1973; 248: 4698
        • Kopelman M
        • Cogan U
        • Mokady S
        • Shinitzky M
        The interaction between retinol-binding proteins and prealbumins studied by fluorescence polarization.
        Biochim Biophys Acta. 1976; 439: 449
        • Smith FR
        • Goodman DS
        The effects of diseases of the liver, thyroid, and kidneys on the transport of vitamin A in human plasma.
        J Clin Invest. 1971; 50: 2426
        • Costa PP
        • Figueira AS
        • Bravo FR
        Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy.
        in: ed. 3. Proc Natl Acad Sci USA. 75. 1978: 4499
        • Tawara S
        • Araki S
        • Toshimori K
        • Nakagowa H
        • Ohtaki S
        Amyloid fibril protein in type I familial amyloidotic polyneuropathy in Japanese.
        J Lab Clin Med. 1981; 98: 811
        • Dalakis MC
        • Engel WK
        Amyloid in hereditary amyloid polyneuropathy is related to prealbumin.
        Arch Neurol. 1981; 38: 420
        • Benson MD
        Partial amino acid sequence homology between an heredofamilial amyloid protein and human plasma prealbumin.
        J Clin Invest. 1981; 67: 1035
        • Skinner M
        • Cohen A
        The prealbumin nature of the amyloid protein in familial amyloid polyneuropathy (FAP)—Swedish variety.
        Biochem Biophys Res Commun. 1981; 99: 1326
        • Pras M
        • Franklin EC
        • Prelli F
        • Frangione B
        A variant of prealbumin from amyloid fibrils in familial polyneuropathy of Jewish origin.
        J Exp Med. 1981; 154: 989
        • Andrade C
        A peculiar form of peripheral neuropathy: familial atypical generalized amyloidosis with special involvement of the peripheral nerves.
        Brain. 1952; 75: 408
        • Costa PP
        • Figueira AS
        • Bravo F
        • Coimbra A
        • Carvalho J
        • Coelho A
        • Ferreira F
        • Barbosa A
        • Andrade C
        Familial amyloidotic polyneuropathy.
        in: Wegelius O Pasternack A Amyloidosis. Academic Press, Inc, New York1976: 183-193
        • Kanai M
        • Raz A
        • Goodman DS
        Retinol-binding protein: the transport protein for vitamin A in human plasma.
        J Clin Invest. 1968; 47: 2025
        • Raz A
        • Goodman DS
        The interaction of thyroxine with human plasma prealbumin and with the prealbumin-retinol binding protein complex.
        J Biol Chem. 1969; 244: 3230
        • Peterson PA
        Studies on the interaction between prealbumin, retinol-binding protein, and vitamin A.
        J Biol Chem. 1971; 246: 44
        • Davis B
        Disc electrophoresis. II. Method and application to human serum proteins.
        Ann NY Acad Sci. 1964; 121: 404
        • Williams DE
        • Reisfeld R
        Disc electrophoresis in polyacrylamide gels: extension to new conditions of pH and buffer.
        Ann NY Acad Sci. 1964; 121: 373
        • Weber K
        • Osborn M
        The reliability of molecular weight determinations by dodecyl sulfate-polyacrylamide electrophoresis.
        J Biol Chem. 1969; 244: 4406
        • Laemmli UK
        Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
        Nature. 1970; 227: 680
        • Wide L
        Use of particulate immunosorbents in radioimmunoassay.
        Methods Enzymol. 1981; 73: 203
        • Heide K
        • Schwick HG
        Salt fractionation of immunoglobulins.
        in: ed. 3. Handbook of Experimental Immunology. vol. 1. Blackwell Scientific Publications, Oxford1978 (chap. 7)
        • Levy HB
        • Sober HA
        A simple chromatographic method for preparation of gamma globulin.
        in: ed. 6. Proc Soc Exp Biol Med. 103. 1960: 250
        • David G
        • Reisfeld R
        Protein iodination with solid state lactoperoxidase.
        Biochemistry. 1974; 13: 1014
        • Kanda Y
        • Goodman DS
        Partial amino acid sequence of human retinol-binding protein. Isolation and alignment of the five cyanogen bromide fragments and the amino acid sequences of 4 of the fragments.
        J Lipid Res. 1979; 20: 865
        • Gawinowicz MA
        • Goodman DS
        Retinoid affinity label for the binding site of retinol-binding protein.
        Biochemistry. 1982; 21: 1899
        • Goodman DS
        • Leslie RB
        Fluorescence studies of human plasma retinol-binding protein and of the retinol-binding protein-prealbumin complex.
        Biochim Biophys Acta. 1972; 260: 670
        • Spackman DH
        • Stein WH
        • Moore S
        Apparatus for use in the chromatography of amino acids.
        Anal Chem. 1958; 30: 1190
        • Mancini G
        • Carbonara AO
        • Heremans JF
        Immunochemical quantitation of antigens by single radial immunodiffusion.
        Immunochemistry. 1965; 2: 235
        • Bradford M
        A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
        Anal Biochem. 1976; 72: 248
        • Bieri J
        • Talliver T
        • Catignani L
        Simultaneous determination of α-tocopherol and retinol in plasma or red cells by high pressure liquid chromatography.
        Am J Clin Nutr. 1979; 32: 2143
        • Snedecor GW
        • Cochran WG
        Statistical Methods.
        ed. 6. Iowa State University Press, Ames, Iowa1967
        • Vahlquist A
        • Sjölund K
        • Nordén Å
        • Peterson PA
        • Stigmar G
        • Johansson B
        Plasma vitamin A transport and visual dark adaptation in diseases of the intestine and liver.
        Scand J Clin Lab Invest. 1978; 38: 301
        • Peterson PA
        Demonstration in serum of two physiological forms of the human retinol-binding protein.
        Eur J Clin Invest. 1971; 1: 437
        • Altland K
        • Rauh S
        • Hackler R
        Demonstration of human prealbumins by double one dimensional slab gel electrophoresis.
        Electrophoresis. 1981; 2: 148
        • Saraiva MJ
        • Costa PP
        • Ferreira PM
        Prealbumin: antigenic properties in the Portuguese type of amyloid neuropathy, Presented at 1st Iberian Congress of Biochemistry. Abst. P-334. 1980
        • Branch W
        • Robbins J
        • Edelhoch H
        Thyroxine-binding prealbumin. Conformation in aqueous solutions.
        J Biol Chem. 1971; 246: 6011
        • Glenner G
        Amyloid deposits and amyloidosis.
        N Engl J Med. 1980; 302: 1283
        • Shoji S
        • Kameba M
        • Tsukada N
        • Kata M
        Immunologic and immunohistochemical study of familial amyloid polyneuropathy.
        Neurology. 1981; 31: 1493
        • Shirahama T
        • Skinner M
        • Westermark P
        • Rubinow A
        • Cohen AS
        • Brun A
        • Kemper TL
        Senile cerebral amyloid. Prealbumin as a common constituent in the neuritic plaque, in the neurofibrillary tangle, and in the microangiopathic lesion.
        Am J Pathol. 1982; 107: 41
        • Sletten K
        • Westermark P
        • Natvig JB
        Senile cardiac amyloid is related to prealbumin.
        Scand J Immunol. 1980; 12: 503
        • Cornwell III, GG
        • Westermark P
        • Natvig JB
        • Murdoch W
        Senile cardiac amyloid: evidence that fibrils contain a protein immunologically related to prealbumin.
        Immunology. 1981; 44: 447
        • Skinner M
        • Heller L
        • Rubinow A
        • Libbey CA
        • Sipe JD
        • Cohen AS
        Depressed serum prealbumin levels in patients with familial amyloid polyneuropathy (FAP) and their non-affected relatives.
        Arthritis Rheum. 1982; 25: S58
        • Benson MD
        • Dwulet FE
        Prealbumin and retinol binding protein levels in heredofamilial amyloidosis.
        Clin Res. 1982; 30: 788A
        • Smith FR
        • Suskind R
        • Thanangkul O
        • Leitzmann C
        • Goodman DS
        • Olson RE
        Plasma vitamin A, retinol-binding protein, and prealbumin concentration in protein-calorie malnutrition. III. Response to varying dietary treatments.
        Am J Clin Nutr. 1975; 28: 732
        • Prandata A
        Immunochemically determined serum prealbumin in hepatitis in children.
        Arch Immunol Ther Exp. 1975; 23: 53
        • Pras M
        • Prelli F
        • Franklin EC
        • Frangione B
        Primary structure of an amyloid prealbumin variant in familial polyneuropathy of Jewish origin.
        in: Proc Natl Acad Sci USA. 801. 1983: 539
        • Saraiva MJ
        • Goodman DS
        • Costa PP
        • Canfield RE
        • Birken S
        Presence of an abnormal transthyretin (prealbumin) in Portuguese patients with familial amyloidotic polyneuropathy.
        Clin Res. 1983; 31: 533A