Takeda K, Balzano S, Sakurai A, DeGroot L J, Refetoff S
Thyroid Study Unit, University of Chicago, Illinois 60637.
J Clin Invest. 1991 Feb;87(2):496-502. doi: 10.1172/JCI115023.
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.
全身性甲状腺激素抵抗（GRTH）是一种以组织对甲状腺激素反应受损为特征的综合征。最近在两个无关的GRTH家族中发现了甲状腺激素受体（TR）β激素结合域中的两个不同的点突变。一个是Mf，涉及外显子7中正常的甘氨酸-345被精氨酸取代；另一个是Mh，涉及外显子8中正常的脯氨酸-453被组氨酸取代。为了探究19个无关的GRTH家族中Mf和Mh缺陷的存在情况，我们使用了分别含有正常核苷酸以及两个突变核苷酸中每一个的3'-位等位基因特异性寡核苷酸引物进行单独的聚合酶链反应。共研究了24名受影响的受试者和13名正常家庭成员。13个家族的遗传模式为显性，5个家族未知，1个家族明显为隐性，其中只有近亲受试者受影响。含有Mf和Mh特异性取代的引物分别仅在两个索引家族中每个家族的受影响成员中扩增出外显子7和8。含有正常序列的引物在除一个家族的受影响成员外的所有受试者中扩增出TRβ基因的外显子7和8。在这个隐性遗传GRTH的家族中，使用任何引物组合都无法扩增出外显子，DNA印迹显示所有编码外显子均缺失。这些结果表明TRβ基因存在主要缺失，包括DNA和激素结合域。由于该家族的杂合成员未受影响，单个正常等位基因的存在足以使TRβ发挥正常功能。这些数据也支持了这样的假设，即在GRTH显性遗传模式中，异常TRβ的存在会干扰正常TRβ的功能。不同的突变可能是无关家族中GRTH的原因。
