Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins
Two de novo mutations in the AR gene cause the complete androgen insensitivity syndrome in a pair of monozygotic twins
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DOI：
10.1210/jc.87.3.1057
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发表时间：
2002-03-01
影响因子：
5.8
通讯作者：
Hughes, IA
中科院分区：
文献类型：
--
作者：
Mongan, NP;Jääskeläinen, J;Hughes, IA
雄激素不敏感综合征 (AIS) 是男性男性化不足的最常见原因，通常由 AR 基因突变引起。受影响的个体可能表现出完全外部女性化（完全AIS）或部分表型（部分AIS）。在这里，我们描述了诊断为完全AIS的同卵双胞胎，每个人都有两个取代（第2930位的C-G和第2955位的T-C，均位于外显子7），分别导致Phe（856）Leu和Ser（865）Pro突变。没有发现父母都是这些突变的携带者，这表明双突变是从头出现的。这两种突变均通过定点诱变重新产生，并与野生型受体进行功能比较。苯丙胺（856）。当在 COS-1 细胞中表达时，Leu 突变不会影响雄激素结合，这种突变也不会降低转染 HeLa 细胞中雄激素依赖性反式激活。然而，Ser(865)。 Pro突变完全消除了雄激素结合和反式激活。在这项研究中，我们证明，865 位的丝氨酸被脯氨酸取代本身就足以在这对双胞胎中引起完全的 AIS。对核受体结构的分析表明，这种突变可能会扰乱螺旋 10/11 的构象，而螺旋 10/11 在配体结合、二聚化和受体激活中发挥作用。据我们所知，这是首例因双胞胎中发生 AR 突变而确诊的 AIS（完全或部分）病例。此外，该表型与两种突变相关，这两种突变本质上都是新颖的。
The androgen insensitivity syndrome (AIS) is the most common cause of male undermasculinization and is typically caused by mutations in the AR gene. Affected individuals may exhibit either complete external feminization (complete AIS) or a partial phenotype (partial AIS). Here we describe monozygotic twins diagnosed with complete AIS who each possess two substitutions (C-G at position 2930 and T-C at position 2955, both in exon 7), leading to Phe(856) Leu and Ser(865)Pro mutations, respectively. Neither parent was found to be a carrier for these mutations, indicating that the double mutation arose de novo. Both mutations were recreated by site-directed mutagenesis and compared functionally with the wild-type receptor. The Phe(856). Leu mutation did not affect androgen binding when expressed in COS-1 cells, nor did this mutation decrease androgen-dependent trans-activation in transfected HeLa cells. However, the Ser(865). Pro mutation completely ablated androgen binding and trans-activation. In this study we demonstrate that the replacement of serine by proline at position 865 is sufficient in itself to cause complete AIS in these twins. Analyses of nuclear receptor structures suggest that this mutation is likely to perturb the conformation of helix 10/11, which plays a role in ligand binding, dimerization, and receptor activation. To our knowledge this is the first confirmed instance of AIS (complete or partial) due to an AR mutation occurring in twins. Furthermore, the phenotype was associated with two mutations that were both novel in nature.