Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene
Complete androgen insensitivity syndrome caused by a deep intronic pseudoexon-activating mutation in the androgen receptor gene
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DOI：
10.1038/srep32819
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发表时间：
2016-09-09
影响因子：
4.6
通讯作者：
Raivio, Taneli
中科院分区：
文献类型：
--
作者：
Kansakoski, Johanna;Jaaskelainen, Jarmo;Raivio, Taneli
X连锁雄激素受体（AR）基因突变是完全雄激素不敏感综合征（CAIS）的基础，CAIS是46，XY性逆转的最常见原因。然而，在AR编码区正常的患者中，CAIS的分子遗传学诊断仍不确定。在这里，我们描述了一种新的机制，AR中断导致CAIS在两个46，XY姐妹篇。我们分析了患者的全基因组测序数据，以确定AR编码区以外的致病性变体。来自生殖器区域的患者成纤维细胞用于AR cDNA分析和蛋白质定量。对cDNA的分析揭示了由AR内含子6中的深度内含子突变（c.2450- 118 A>G）引起的mRNA的异常剪接。该突变产生了一个从头5'剪接位点和一个推定的外显子剪接增强子基序，这导致优先形成两个异常剪接的mRNA（预测包括一个提前终止密码子）。患者成纤维细胞未检测到AR蛋白。我们的研究结果表明，CAIS和正常AR编码区的患者需要检查可导致假外显子激活的深度内含子突变。
Mutations in the X-linked androgen receptor (AR) gene underlie complete androgen insensitivity syndrome (CAIS), the most common cause of 46, XY sex reversal. Molecular genetic diagnosis of CAIS, however, remains uncertain in patients who show normal coding region of AR. Here, we describe a novel mechanism of AR disruption leading to CAIS in two 46, XY sisters. We analyzed whole-genome sequencing data of the patients for pathogenic variants outside the AR coding region. Patient fibroblasts from the genital area were used for AR cDNA analysis and protein quantification. Analysis of the cDNA revealed aberrant splicing of the mRNA caused by a deep intronic mutation (c.2450-118A>G) in the intron 6 of AR. The mutation creates a de novo 5' splice site and a putative exonic splicing enhancer motif, which leads to the preferential formation of two aberrantly spliced mRNAs (predicted to include a premature stop codon). Patient fibroblasts contained no detectable AR protein. Our results show that patients with CAIS and normal AR coding region need to be examined for deep intronic mutations that can lead to pseudoexon activation.