Reduced affinity for thyroxine in two of three structural thyroxine-binding prealbumin variants associated with familial amyloidotic polyneuropathy

S. Refetoff, F. E. Dwulet, Merrill Benson

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Abstract

T4-binding prealbumin (TBPA), a protein synthesized by the liver, circulates as a tetramer and transports 15-20% of T4. We studied 3 variants of the TBPA monomer recently identified in serum and amyloid fibrils of patients affected by familial amyloidotic polyneuropathy (FAP). They represent single amino acid substitutions at positions 30 (type I), 60 (Appalachian), and 84 (type II). Tests of thyroid function and the apparent association constant (K(a)) of T4 binding to TBPA were measured in whole serum from 14 carriers of FAP identified clinically, by amino acid sequence analysis, or by DNA restriction fragment analysis. Significant reduction of K(a) was found in subjects with FAP types I and II, but not in subjects with the Appalachian type. Mean (± SD) values of 0.24 ± 0.08 x 107 M-1 for type I and 0.26 ± 0.10 x 107 M-1 for type II were significantly (P <0.0001) lower than those for normal relatives (1.39 ± 0.30 x 107 M-1) or unrelated normal subjects (1.41 ± 0.18 x 107 M-1). The mean K(a) value for the five subjects with FAP of the Appalachian type was slightly but not significantly reduced (1.08 ± 0.11 x 107 M-1). There was no overlap of individual K(a) values of subjects with types I and II TBPA with those of subjects from all other groups. Abnormalities of thyroid function included slight but significant reductions of the mean total serum T4 concentration in the subjects with type II FAP and the mean serum total T3 concentration in those with type I FAP. Four subjects with FAP (two type II and two of the Appalachian type) had biochemical evidence of hypothyroidism. The three subjects with total serum T3 levels below the limit of normal had amyloid cardiomyopathy. These results indicate that TBPAs from subjects with FAP types I and II have relatively lower affinity for T4. Although none of the substituted amino acids in these variant TBPAs contribute directly to the surface of the putative T4-binding site, the side chains of amino acids 30 and 84, but not 60, interact with internal residues of the β-structure which forms the presumed binding site, in agreement with our results of K(a) measurements. The high incidence of hypothyroidism is due to the probably fortuitous occurrence of Hashimoto's thyroiditis as well as to partial destruction of the thyroid gland by amyloid deposits.

Original languageEnglish (US)
Pages (from-to)1432-1437
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume63
Issue number6
StatePublished - 1986

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Prealbumin
Polyneuropathies
Thyroxine
Amyloid
Amino Acids
Binding Sites
Serum
Hypothyroidism
Liver
Thyroid Gland
Substitution reactions
Deposits
Monomers
Association reactions
Thyroid Function Tests
Hashimoto Disease
DNA
Protein Sequence Analysis
Amyloid Plaques
Amino Acid Substitution

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{99c0fa52858f47e9b667335a50eb1c82,
title = "Reduced affinity for thyroxine in two of three structural thyroxine-binding prealbumin variants associated with familial amyloidotic polyneuropathy",
abstract = "T4-binding prealbumin (TBPA), a protein synthesized by the liver, circulates as a tetramer and transports 15-20{\%} of T4. We studied 3 variants of the TBPA monomer recently identified in serum and amyloid fibrils of patients affected by familial amyloidotic polyneuropathy (FAP). They represent single amino acid substitutions at positions 30 (type I), 60 (Appalachian), and 84 (type II). Tests of thyroid function and the apparent association constant (K(a)) of T4 binding to TBPA were measured in whole serum from 14 carriers of FAP identified clinically, by amino acid sequence analysis, or by DNA restriction fragment analysis. Significant reduction of K(a) was found in subjects with FAP types I and II, but not in subjects with the Appalachian type. Mean (± SD) values of 0.24 ± 0.08 x 107 M-1 for type I and 0.26 ± 0.10 x 107 M-1 for type II were significantly (P <0.0001) lower than those for normal relatives (1.39 ± 0.30 x 107 M-1) or unrelated normal subjects (1.41 ± 0.18 x 107 M-1). The mean K(a) value for the five subjects with FAP of the Appalachian type was slightly but not significantly reduced (1.08 ± 0.11 x 107 M-1). There was no overlap of individual K(a) values of subjects with types I and II TBPA with those of subjects from all other groups. Abnormalities of thyroid function included slight but significant reductions of the mean total serum T4 concentration in the subjects with type II FAP and the mean serum total T3 concentration in those with type I FAP. Four subjects with FAP (two type II and two of the Appalachian type) had biochemical evidence of hypothyroidism. The three subjects with total serum T3 levels below the limit of normal had amyloid cardiomyopathy. These results indicate that TBPAs from subjects with FAP types I and II have relatively lower affinity for T4. Although none of the substituted amino acids in these variant TBPAs contribute directly to the surface of the putative T4-binding site, the side chains of amino acids 30 and 84, but not 60, interact with internal residues of the β-structure which forms the presumed binding site, in agreement with our results of K(a) measurements. The high incidence of hypothyroidism is due to the probably fortuitous occurrence of Hashimoto's thyroiditis as well as to partial destruction of the thyroid gland by amyloid deposits.",
author = "S. Refetoff and Dwulet, {F. E.} and Merrill Benson",
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TY - JOUR

T1 - Reduced affinity for thyroxine in two of three structural thyroxine-binding prealbumin variants associated with familial amyloidotic polyneuropathy

AU - Refetoff, S.

AU - Dwulet, F. E.

AU - Benson, Merrill

PY - 1986

Y1 - 1986

N2 - T4-binding prealbumin (TBPA), a protein synthesized by the liver, circulates as a tetramer and transports 15-20% of T4. We studied 3 variants of the TBPA monomer recently identified in serum and amyloid fibrils of patients affected by familial amyloidotic polyneuropathy (FAP). They represent single amino acid substitutions at positions 30 (type I), 60 (Appalachian), and 84 (type II). Tests of thyroid function and the apparent association constant (K(a)) of T4 binding to TBPA were measured in whole serum from 14 carriers of FAP identified clinically, by amino acid sequence analysis, or by DNA restriction fragment analysis. Significant reduction of K(a) was found in subjects with FAP types I and II, but not in subjects with the Appalachian type. Mean (± SD) values of 0.24 ± 0.08 x 107 M-1 for type I and 0.26 ± 0.10 x 107 M-1 for type II were significantly (P <0.0001) lower than those for normal relatives (1.39 ± 0.30 x 107 M-1) or unrelated normal subjects (1.41 ± 0.18 x 107 M-1). The mean K(a) value for the five subjects with FAP of the Appalachian type was slightly but not significantly reduced (1.08 ± 0.11 x 107 M-1). There was no overlap of individual K(a) values of subjects with types I and II TBPA with those of subjects from all other groups. Abnormalities of thyroid function included slight but significant reductions of the mean total serum T4 concentration in the subjects with type II FAP and the mean serum total T3 concentration in those with type I FAP. Four subjects with FAP (two type II and two of the Appalachian type) had biochemical evidence of hypothyroidism. The three subjects with total serum T3 levels below the limit of normal had amyloid cardiomyopathy. These results indicate that TBPAs from subjects with FAP types I and II have relatively lower affinity for T4. Although none of the substituted amino acids in these variant TBPAs contribute directly to the surface of the putative T4-binding site, the side chains of amino acids 30 and 84, but not 60, interact with internal residues of the β-structure which forms the presumed binding site, in agreement with our results of K(a) measurements. The high incidence of hypothyroidism is due to the probably fortuitous occurrence of Hashimoto's thyroiditis as well as to partial destruction of the thyroid gland by amyloid deposits.

AB - T4-binding prealbumin (TBPA), a protein synthesized by the liver, circulates as a tetramer and transports 15-20% of T4. We studied 3 variants of the TBPA monomer recently identified in serum and amyloid fibrils of patients affected by familial amyloidotic polyneuropathy (FAP). They represent single amino acid substitutions at positions 30 (type I), 60 (Appalachian), and 84 (type II). Tests of thyroid function and the apparent association constant (K(a)) of T4 binding to TBPA were measured in whole serum from 14 carriers of FAP identified clinically, by amino acid sequence analysis, or by DNA restriction fragment analysis. Significant reduction of K(a) was found in subjects with FAP types I and II, but not in subjects with the Appalachian type. Mean (± SD) values of 0.24 ± 0.08 x 107 M-1 for type I and 0.26 ± 0.10 x 107 M-1 for type II were significantly (P <0.0001) lower than those for normal relatives (1.39 ± 0.30 x 107 M-1) or unrelated normal subjects (1.41 ± 0.18 x 107 M-1). The mean K(a) value for the five subjects with FAP of the Appalachian type was slightly but not significantly reduced (1.08 ± 0.11 x 107 M-1). There was no overlap of individual K(a) values of subjects with types I and II TBPA with those of subjects from all other groups. Abnormalities of thyroid function included slight but significant reductions of the mean total serum T4 concentration in the subjects with type II FAP and the mean serum total T3 concentration in those with type I FAP. Four subjects with FAP (two type II and two of the Appalachian type) had biochemical evidence of hypothyroidism. The three subjects with total serum T3 levels below the limit of normal had amyloid cardiomyopathy. These results indicate that TBPAs from subjects with FAP types I and II have relatively lower affinity for T4. Although none of the substituted amino acids in these variant TBPAs contribute directly to the surface of the putative T4-binding site, the side chains of amino acids 30 and 84, but not 60, interact with internal residues of the β-structure which forms the presumed binding site, in agreement with our results of K(a) measurements. The high incidence of hypothyroidism is due to the probably fortuitous occurrence of Hashimoto's thyroiditis as well as to partial destruction of the thyroid gland by amyloid deposits.

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