Mixson A J, Renault J C, Ransom S, Bodenner D L, Weintraub B D
Molecular and Cellular Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health 20892.
Clin Endocrinol (Oxf). 1993 Mar;38(3):227-34. doi: 10.1111/j.1365-2265.1993.tb00999.x.
We investigated whether the first patient (L-F3) reported as having selective pituitary resistance had a mutation in the hTR beta gene. We compared the clinical parameters of this case with those of patients with generalized resistance to thyroid hormone.
The patient, L-F3, was part of a study at the NIH to identify mutations by sequencing the hTR beta gene in kindreds with thyroid hormone resistance. The clinical data of L-F3 as well as patients with generalized resistance to thyroid hormone were compared and analysed retrospectively.
We amplified by the polymerase chain reaction and then sequenced exons 5 to 10 of the hTR beta gene in L-F3 and a normal control. Upon finding the mutation in L-F3, we measured the affinity constant of this mutated hTR beta receptor. Criteria developed previously were used to assess tissue responsiveness to thyroid hormone of L-F3.
We identified a C to T transition at base 1297 in codon 333 of the hTR beta gene in the first patient (L-F3) reported as having apparent selective pituitary resistance. This base substitution resulted in more than a four-fold decrease in T3-binding affinity for the hTR beta 1 receptor. The mutation of L-F3 occurred in the dimerization domain of exon 9, a region where the majority of mutations of kindreds with generalized thyroid hormone resistance have been found. Furthermore, the nucleotide substitution at base 1297 found in the apparent selective pituitary resistant case, L-F3, was the same as in an unrelated patient (K-T3) with generalized resistance to thyroid hormone. As a result, we compared the clinical parameters of both patients and found that they had similar patterns of resistance in several tissues. Besides the bone resistance present in both kindreds, the apparent selective pituitary resistance case also had liver and neuromuscular resistance.
These findings suggest that apparent selective pituitary resistance and generalized resistance to thyroid hormone are not qualitatively different syndromes. Nevertheless, identification of selective pituitary resistance is a useful clinical distinction since such patients with clinical and biochemical features of hyperthyroidism appear to benefit from reduction in serum thyroid hormone concentrations. In contrast, patients with more conventional forms of thyroid hormone resistance require no treatment or may benefit from increased concentrations of thyroid hormone.
我们研究了首例被报道患有选择性垂体抵抗的患者（L-F3）的hTRβ基因是否存在突变。我们将该病例的临床参数与甲状腺激素全身性抵抗患者的参数进行了比较。
患者L-F3是美国国立卫生研究院（NIH）一项研究的一部分，该研究旨在通过对甲状腺激素抵抗家族中的hTRβ基因进行测序来鉴定突变。对L-F3以及甲状腺激素全身性抵抗患者的临床数据进行回顾性比较和分析。
我们通过聚合酶链反应进行扩增，然后对L-F3和一名正常对照者的hTRβ基因第5至10外显子进行测序。在L-F3中发现突变后，我们测量了这种突变的hTRβ受体的亲和常数。使用先前制定的标准来评估L-F3对甲状腺激素的组织反应性。
我们在首例被报道患有明显选择性垂体抵抗的患者（L-F3）的hTRβ基因第333密码子的1297位碱基处发现了C到T的转换。这种碱基替换导致hTRβ1受体对T3的结合亲和力下降了四倍多。L-F3的突变发生在外显子9的二聚化结构域，在甲状腺激素全身性抵抗家族的大多数突变中都发现了该区域。此外，在明显的选择性垂体抵抗病例L-F3中发现的1297位碱基的核苷酸替换与一名患有甲状腺激素全身性抵抗的无关患者（K-T3）相同。因此，我们比较了两名患者的临床参数，发现他们在多个组织中的抵抗模式相似。除了两个家族都存在的骨骼抵抗外，明显的选择性垂体抵抗病例还存在肝脏和神经肌肉抵抗。
这些发现表明，明显的选择性垂体抵抗和甲状腺激素全身性抵抗并非性质不同的综合征。然而，识别选择性垂体抵抗是一种有用的临床区分，因为这类具有甲状腺功能亢进临床和生化特征的患者似乎可从血清甲状腺激素浓度降低中获益。相比之下，具有更传统形式甲状腺激素抵抗的患者无需治疗，或可能从甲状腺激素浓度升高中获益。
