Usala S J, Wondisford F E, Watson T L, Menke J B, Weintraub B D
Department of Medicine, East Carolina University School of Medicine, Greenville, North Carolina 27858-4354.
Biochem Biophys Res Commun. 1990 Sep 14;171(2):575-80. doi: 10.1016/0006-291x(90)91185-u.
We have previously reported a family, Kindred A, with autosomal dominant generalized thyroid hormone resistance in which affected members were found to have a mutation in the carboxy-terminal domain of the c-erbA beta thyroid hormone receptor. In the current study, the thyroid hormone and DNA-binding properties of this mutant receptor were determined using c-erbA beta protein synthesized in vitro. Both the wild-type human placental c-erbA beta and Kindred A receptors bound [125I]-triiodothyronine, although the Kindred A receptor had decreased affinity for the hormone. The affinity for triiodothyronine was 4.5 x 10(9) M-1 and 2.3 x 10(10) M-1 for the mutant and wild-type receptors, respectively. No abnormality of DNA-binding was detected with the Kindred A receptor using a sensitive avidin-biotin DNA-binding assay with DNA fragments containing thyroid hormone response elements. The Kindred A mutant receptor which displays abnormal triiodothyronine-binding but normal DNA-binding activities in vitro acts as a dominant negative inhibitor of thyroid hormone action in man.
我们之前报道过一个家系（A系），其患有常染色体显性遗传的全身性甲状腺激素抵抗，在家系中受影响的成员被发现其c-erbAβ甲状腺激素受体的羧基末端结构域存在突变。在当前研究中，使用体外合成的c-erbAβ蛋白测定了该突变受体的甲状腺激素及DNA结合特性。野生型人胎盘c-erbAβ和A系受体均可结合[125I]-三碘甲状腺原氨酸，尽管A系受体对该激素的亲和力有所降低。突变型和野生型受体对三碘甲状腺原氨酸的亲和力分别为4.5×10⁹M⁻¹和2.3×10¹⁰M⁻¹。使用含有甲状腺激素反应元件的DNA片段进行的灵敏抗生物素蛋白-生物素DNA结合试验未检测到A系受体的DNA结合异常。在体外表现出异常三碘甲状腺原氨酸结合但正常DNA结合活性的A系突变受体，在人体中作为甲状腺激素作用的显性负性抑制剂发挥作用。
