MUTATIONS OF THE THYROID HORMONE RECEPTOR GENE IN THYROID HORMONE RESISTANCE

甲状腺激素全身性抵抗(Grth)是一种遗传病 与βT3受体基因的突变有关，并表征了 临床上由外周和垂体组织对 甲状腺激素的作用。在已确定的30多种不同的突变中 在β受体的配基结合域中，有几个被证明是 通过显性的负性机制抑制正常的受体功能 可能在这种疾病的表型中起中介作用。最近的研究表明 表明这种显性的负面影响很可能是由 突变型受体与正常受体竞争结合T3反应 各种甲状腺激素反应基因中的元素。 我们最近还调查了这种异质性表型 在家庭内部和家庭之间出现的特征可能是由于差异 突变受体与正常受体在不同组织中的表达。使用 等位基因特异性引物延伸法，我们已经确定了在某些 患者体内有大量的突变信使RNA的表达 这可能与更严重的组织耐药性有关。该机制的目的是 目前正在对这种差异表达进行研究。 我们还研究了Grth和注意力之间的关系 缺乏性多动障碍。我们研究了一大群井。 特征患者包括49个受影响的家庭和55个未受影响的家庭 成员包括52名成年人和52名儿童。注意力缺陷 70%的受影响儿童存在多动症，而 20%的未受影响的家庭成员。此外，甲状腺激素治疗 似乎可以改善某些患者的多动症状。 某些患有多动症的患者也进行了研究。 通过正电子发射断层扫描。在正电子测量的60个区域中 发射断层扫描，葡萄糖代谢率明显降低 在右上顶叶，在枕中叶增加 提示糖代谢的这种变化可能与 持续注意力的异常。 这些数据表明，注意力缺陷多动障碍是 与全身性甲状腺抵抗有强烈和特殊的关联 荷尔蒙。这是第一个定义的多动症的分子模型 可能为这种疾病的基本发病机制提供新的见解。

Generalized resistance to thyroid hormone (GRTH) is an inherited disease linked to mutations in the beta T3 receptor gene and characterized clinically by the resistance of peripheral and pituitary tissues to the action of thyroid hormone. Of the over 30 different mutations identified in the ligand binding domain of the beta receptor, several were shown to inhibit normal receptor function by a dominant negative mechanism which is likely to mediate the phenotype of this disease. Recent studies have indicated that this dominant negative effect is most likely mediated by competition of mutant and normal receptor for binding to T3 response elements within various thyroid hormone responsive genes. We have also recently investigated whether the heterogeneous phenotypic features that occur within and among kindreds might be due to differential expression of mutant vs. normal receptors in various tissues. Using an allele-specific primer extension method, we have determined that in certain patients there is a great excess of expression of the mutant messenger RNA which may correlate with more severe tissue resistance. The mechanism for such differential expression is currently being examined. We have also investigated the relationship between GRTH and attention deficit hyperactivity disorder. We studied a large population of well characterized patients consisting of 49 affected and 55 unaffected family members comprising a total of 52 adults and 52 children. Attention deficit hyperactivity disorder was found in 70% of affected children compared to 20% of unaffected family members. In addition, thyroid hormone therapy appeared to ameliorate the hyperactivity symptoms in certain patients. Certain of the patients with the hyperactivity disorder were also studied by positron emission tomography. Of the 60 regions measured by positron emission tomography, glucose metabolic rates were significantly decreased in the superior right parietal lobes and increased in the mid-occipital lobes, suggesting that such changes in glucose metabolism may be related to abnormalities of sustained attention. These data demonstrate that an attention deficit hyperactivity disorder is strongly and specifically associated with generalized resistance to thyroid hormone. This is the first defined molecular model of hyperactivity and may provide new insights into the basic pathogenesis of this disorder.