CHARACTERIZATION OF 7 NOVEL MUTATIONS OF THE C-ERBA-BETA GENE IN UNRELATED KINDREDS WITH GENERALIZED THYROID-HORMONE RESISTANCE - EVIDENCE FOR 2 HOT-SPOT REGIONS OF THE LIGAND-BINDING DOMAIN
CHARACTERIZATION OF 7 NOVEL MUTATIONS OF THE C-ERBA-BETA GENE IN UNRELATED KINDREDS WITH GENERALIZED THYROID-HORMONE RESISTANCE - EVIDENCE FOR 2 HOT-SPOT REGIONS OF THE LIGAND-BINDING DOMAIN
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DOI：
10.1172/jci115542
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发表时间：
1991-12-01
影响因子：
15.9
通讯作者：
WEINTRAUB, BD
中科院分区：
文献类型：
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作者：
PARRILLA, R;MIXSON, AJ;WEINTRAUB, BD
在我们实验室对全身性甲状腺激素抵抗（GTHR）家族的遗传分析表明，与编码核T3受体的基因座c-erbA-β紧密连锁。在这个位点的三个点突变和两个缺失以前曾报道在受影响的个人在无关的家庭作为潜在的分子基础，这种疾病。在本研究中，我们使用了直接测序的聚合酶链反应扩增的c-erbA-β基因的外显子，以快速确定新的点突变，从7个以前未表征的激酶与GTHR。鉴定了六个单碱基取代和一个单碱基插入，并发现其聚集在受体配体结合结构域中外显子9和10的两个区域中：在远端配体结合亚结构域L2中以及跨tau（i）和二聚化亚结构域的接合处。T3结合亲和力的减少，在每个测试的四个突变，以及分离的所有突变的临床受影响的个人强烈支持的假设，这些变化是GTHR在这些激酶的原因。鉴于临床表现型的多样性，突变的独特地形聚类为甲状腺受体功能的分子解剖提供了宝贵的遗传工具。
Genetic analysis in our laboratory of families with generalized thyroid hormone resistance (GTHR) has demonstrated tight linkage with a locus, c-erbA-beta, encoding a nuclear T3 receptor. Three point mutations and two deletions in this locus have previously been reported in affected individuals in unrelated families as potential molecular bases for this disorder. In the present study, we have used direct sequencing of polymerase chain reaction-amplified exons of the c-erbA-beta gene to rapidly identify novel point mutations from seven previously uncharacterized kindreds with GTHR. Six single base substitutions and one single base insertion were identified and found to be clustered in two regions of exons 9 and 10 in the ligand binding domain of the receptor: in the distal ligand-binding subdomain L2 and across the juncture of the tau(i) and dimerization subdomains. Reduction of T3-binding affinity in each of four mutations tested as well as segregation of all mutations to clinically affected individuals strongly supports the hypothesis that these changes are the cause of GTHR in these kindreds. In view of the diversity of clinical phenotypes manifested, the distinct topographic clustering of the mutations provides an invaluable genetic tool for the molecular dissection of thyroid receptor function.