Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation.
Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation.
复制标题
对 19 个对甲状腺激素普遍耐药的无关家庭进行甲状腺激素受体 β 基因已知点突变的筛查，并检测新的突变。
DOI：
10.1172/jci115023
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发表时间：
1991
期刊：
影响因子：
--
通讯作者：
Refetoff,S
中科院分区：
文献类型：
--
作者：
Takeda,K;Balzano,S;Sakurai,A;DeGroot,LJ;Refetoff,S
甲状腺激素全身抵抗（GRTH）是一种以组织对甲状腺激素的反应性受损为特征的综合征。最近在两个不相关的GRTH家族中发现了甲状腺激素受体（TR）β的激素结合结构域中的两个不同的点突变。一个是Mf，涉及外显子7中精氨酸的正常甘氨酸-345的替换，另一个是Mh，外显子8中组氨酸的正常脯氨酸-453的替换。为了检测19个不相关的GRTH家族中Mf和Mh缺陷的存在，我们应用单独的聚合酶链反应，使用等位基因特异性寡核苷酸引物，在3 '位含有正常和两个突变核苷酸。共有24名受影响的受试者和13名正常家庭成员进行了研究。13个家系的遗传方式为显性，5个家系的遗传方式不明，1个家系的遗传方式明显为隐性，且仅影响近亲。引物含有特异性Mf和Mh扩增外显子7和8，分别，只有在受影响的成员的两个指数的家庭。含有正常序列的引物扩增TR β基因的外显子7和8在所有受试者中，除了一个家庭的受影响成员。在这个家族中，没有外显子可以扩增使用任何组合的引物和DNA印迹显示所有编码外显子的情况下。这些结果表明TR β基因的主要缺失，包括DNA和激素结合结构域。由于该家族的杂合子成员不受影响，因此单个正常等位基因的存在足以使TR β发挥正常功能。这些数据也支持这样的假设，即在GRTH遗传的显性模式中，异常TR β的存在干扰了正常TR β的功能。不同的突变可能是无关家族中GRTH的原因。图片
Generalized resistance to thyroid hormone (GRTH) is a syndrome characterized by impaired tissue responsiveness to thyroid hormone. Two distinct point mutations in the hormone binding domain of the thyroid hormone receptor (TR) beta have recently been identified in two unrelated families with GRTH. One, Mf, involves a replacement of the normal glycine-345 for arginine in exon 7 and another, Mh, replaces the normal proline-453 for histidine in exon 8. To probe for the presence of the Mf and Mh defect in 19 unrelated families with GRTH, we applied separate polymerase chain reactions using allele-specific oligonucleotide primers containing the normal and each of the two mutant nucleotides at the 3'-position. A total of 24 affected subjects and 13 normal family members were studied. The mode of inheritance was dominant in 13 families, was unknown in 5 families, and was clearly recessive in 1 family in which only the consanguineous subjects were affected. Primers containing the substitutions specific for Mf and Mh amplified exons 7 and 8, respectively, only in affected members of each of the two index families. Primers containing the normal sequences amplified exons 7 and 8 of the TR beta gene in all subjects except affected members of one family. In this family with recessively inherited GRTH, neither exon could be amplified using any combinations of primers and DNA blot revealed absence of all coding exons. These results indicate a major deletion of the TR beta gene, including both DNA and hormone binding domains. Since heterozygous members of this family are not affected, the presence of a single normal allele is sufficient for normal function of the TR beta. These data also support the hypothesis that in the dominant mode of GRTH inheritance the presence of an abnormal TR beta interferes with the function of the normal TR beta. Distinct mutations are probably responsible for GRTH in unrelated families.Images