Refetoff S, Dwulet F E, Benson M D
J Clin Endocrinol Metab. 1986 Dec;63(6):1432-7. doi: 10.1210/jcem-63-6-1432.
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 (Ka) 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 Ka 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 10(7) M-1 for type I and 0.26 +/- 0.10 X 10(7) M-1 for type II were significantly (P less than 0.0001) lower than those for normal relatives (1.39 +/- 0.30 X 10(7) M-1) or unrelated normal subjects (1.41 +/- 0.18 X 10(7) M-1). The mean Ka value for the five subjects with FAP of the Appalachian type was slightly but not significantly reduced (1.08 +/- 0.11 X 10(7) M-1). There was no overlap of individual Ka 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 beta-structure which forms the presumed binding site, in agreement with our results of Ka 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.
甲状腺素结合前白蛋白（TBPA）是一种由肝脏合成的蛋白质，以四聚体形式循环并运输15% - 20%的甲状腺素（T4）。我们研究了最近在家族性淀粉样多神经病（FAP）患者的血清和淀粉样纤维中鉴定出的TBPA单体的3种变体。它们分别代表第30位（I型）、60位（阿巴拉契亚型）和84位（II型）的单个氨基酸取代。通过临床鉴定、氨基酸序列分析或DNA限制性片段分析，对14名FAP携带者的全血清进行了甲状腺功能测试以及T4与TBPA结合的表观缔合常数（Ka）的测定。发现I型和II型FAP患者的Ka值显著降低，但阿巴拉契亚型患者的Ka值未降低。I型的平均（±标准差）值为0.24±0.08×10⁷ M⁻¹，II型为0.26±0.10×10⁷ M⁻¹，显著低于正常亲属（1.39±0.30×10⁷ M⁻¹）或无关正常受试者（1.41±0.18×10⁷ M⁻¹）（P＜0.0001）。5名阿巴拉契亚型FAP患者的平均Ka值略有降低但不显著（1.08±0.11×10⁷ M⁻¹）。I型和II型TBPA患者的个体Ka值与所有其他组的个体Ka值没有重叠。甲状腺功能异常包括II型FAP患者血清总T4浓度平均值略有但显著降低，I型FAP患者血清总T3浓度平均值降低。4名FAP患者（2名II型和2名阿巴拉契亚型）有甲状腺功能减退的生化证据。3名血清总T3水平低于正常下限的患者患有淀粉样心肌病。这些结果表明，I型和II型FAP患者的TBPA对T4的亲和力相对较低。尽管这些变体TBPA中没有一个取代氨基酸直接作用于假定的T4结合位点表面，但30位和84位氨基酸的侧链而非60位氨基酸的侧链与形成假定结合位点的β结构内部残基相互作用，这与我们的Ka测量结果一致。甲状腺功能减退的高发生率可能是由于桥本甲状腺炎的偶然发生以及淀粉样沉积物对甲状腺的部分破坏。
