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Reduced Affinity for Thyroxine in Two of Three Structural Thyroxine-Binding Prealbumin Variants Associated with Familial Amyloidotic Polyneuropathy^*

Thyroid Study Unit, Departments of Medicine and Pediatrics, University of Chicago Chicago, Illinois 60637
The Rheumatology Section, Richard L. Roudebush Veterans Administration Medical Center Indianapolis, Indiana 46223
Departments of Medicine, Biochemistry, and Medical Genetics, Indiana University School of Medicine Indianapolis, Indiana 46223

Address requests for reprints to: Dr. Samuel Refetoff, Thyroid Study Unit, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637.

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 0⁷ 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.

^* Presented in part at the 15th Annual Meeting of the European Thyroid Association, Stockholm, Sweden, June 30 to July 4, 1986. This work was supported in part by USPHS Grants AM-15070 (to S.R.). F.E.D. and M.D.B. received support from USPHS Grants AM-20582, M-7448, and RR-750, V.A. Medical Research Grant MR15 583–0888, the Arthritis Foundation, the Grace M. Showalter Trust, the Marion E. Jacobson Fund, the National Science Foundation, and Sigma Xi.

Received June 10, 1986.