GENETIC-ANALYSIS OF 29 KINDREDS WITH GENERALIZED AND PITUITARY RESISTANCE TO THYROID-HORMONE - IDENTIFICATION OF 13 NOVEL MUTATIONS IN THE THYROID-HORMONE RECEPTOR-BETA GENE
GENETIC-ANALYSIS OF 29 KINDREDS WITH GENERALIZED AND PITUITARY RESISTANCE TO THYROID-HORMONE - IDENTIFICATION OF 13 NOVEL MUTATIONS IN THE THYROID-HORMONE RECEPTOR-BETA GENE
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DOI：
10.1172/jci117362
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发表时间：
1994-08-01
影响因子：
15.9
通讯作者：
CHATTERJEE, KK
中科院分区：
文献类型：
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作者：
ADAMS, M;MATTHEWS, C;CHATTERJEE, KK
甲状腺激素抵抗(RTH)，血清游离甲状腺激素水平升高，促甲状腺激素水平未受抑制，要么相对无症状，提示为全身性疾病(GRTH)，要么与甲状腺功能亢进有关，提示可能是选择性垂体抵抗(PRTH)。对散发性或显性遗传的20例GRTH和9例PRTH进行了分析。除了一例七核苷酸插入外，受影响的个体在甲状腺激素受体β基因中的单核苷酸替换是杂合的。除了一个例外，相应的13个新密码子和7个已知密码子变化定位于受体激素结合区域中的两个突变簇，并扩展了它们的边界。15个家系共有6个不同的突变，突变等位基因的单倍型分析表明它们是独立发生的。大多数(19个中的14个)复发，但少数(10个中的1个)独特突变是CpG二核苷酸的过渡。突变的受体与配体的结合受到中度或严重的损害，与甲状腺功能障碍的程度无关。临床特征与受体突变的性质或位置之间没有关联。这些观察表明Grth和PRTH是同一遗传疾病的表型变异，其临床表达可能受到其他非突变相关因素的调节。
Resistance to thyroid hormone (RTH), with elevated serum free thyroid hormones and nonsuppressed thyrotropin levels, is either relatively asymptomatic, suggesting a generalized disorder (GRTH) or associated with thyrotoxic features, indicating possible selective pituitary resistance (PRTH). 20 GRTH and 9 PRTH cases, sporadic or dominantly inherited, were analyzed. Affected individuals were heterozygous for single nucleotide substitutions in the thyroid hormone receptor beta gene, except for a single case of a seven nucleotide insertion. With one exception, the corresponding 13 novel and 7 known codon changes localized to and extended the boundaries of two mutation clusters in the hormone-binding domain of the receptor. 15 kindreds shared 6 different mutations, and haplotype analyses of the mutant allele showed that they occurred independently. The majority (14 out of 19) of the recurrent but a minority (1 out of 10) of unique mutations were transitions of CpG dinucleotides. Mutant receptor binding to ligand was moderately or severely impaired and did not correlate with the magnitude of thyroid dysfunction. There was no association between clinical features and the nature or location of a receptor mutation. These observations suggest that GRTH and PRTH are phenotypic variants of the same genetic disorder, whose clinical expression may be modulated by other non-mutation-related factors.