One Novel and Two Recurrent THRB Mutations Associated with Resistance to Thyroid Hormone: Structure-based Computational Mutation Prediction.
One Novel and Two Recurrent THRB Mutations Associated with Resistance to Thyroid Hormone: Structure-based Computational Mutation Prediction.
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DOI：
10.1297/cpe.19.91
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Hasegawa T
中科院分区：
文献类型：
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作者：
Narumi S;Cho H;Tamada I;Kozu Y;Tsuchiya T;Nagai T;Hasegawa T
编码甲状腺激素受体β(TRRTH)的THRB基因的失活突变会导致对甲状腺激素的抵抗(β；OMIM 190160)。到目前为止，在RTH患者中已经报告了100多个THRB突变。大多数突变都替换了配体结合域中的一个氨基酸残基。在这份报告中，我们描述了三个RTH家系的临床和分子表现。3个家系携带1个新的THRB突变(p.I431M)和2个复发性突变(p.R320H和p.R383C)。为了检测已识别突变的致病性，我们介绍了一种新的基于TRβ-T3复合体三维结构数据的计算突变预测方法。首先，为了确定我们预测系统的准确性，我们评估了之前报道的10个“阳性对照”突变，以及作为“阴性对照”观察到的30个脊椎物种间看似良性的序列变异。我们发现我们的系统有80%的灵敏度和93%的特异度。然后，我们分析了目前研究中检测到的三种突变，发现所有这三种突变都被预测是有害的。我们的数据表明，我们的基于结构的预测系统将是一种快速、廉价和可行的方法来评估THRB错义突变的致病性。
Inactivating mutations of THRB, which encodes the thyroid hormone receptor β (TRβ), cause resistance to thyroid hormone (RTH; OMIM 190160). To date, more than 100 THRB mutations have been reported among RTH patients. Most mutations substitute a single amino-acid residue in the ligand-binding domain. In this report, we describe clinical and molecular findings of three families with RTH. Three families harbored one novel (p.I431M) and two recurrent (p.R320H and p.R383C) THRB mutations. To examine the pathogenicity of identified mutations, we introduced a novel computational mutation prediction method based on three-dimensional structure data of TRβ-T3 complex. First, to define the accuracy of our prediction system, we evaluated ten previously reported ‘positive control’ mutations, as well as 30 seemingly benign sequence variations observed among vertebral species as ‘negative controls’. We found that our system had a sensitivity of 80% and a specificity of 93%. We then analyzed three mutations detected in the present study and found that all three mutations are predicted to be deleterious. Our data suggest that our structure-based prediction system would be a prompt, inexpensive and feasible method for evaluating the pathogenicity of missense THRB mutations.