Functional analysis of SOX10 mutations identified in Chinese patients with Kallmann syndrome
Functional analysis of SOX10 mutations identified in Chinese patients with Kallmann syndrome
复制标题
中国卡尔曼综合征患者 SOX10 突变的功能分析
DOI：
10.1016/j.gene.2019.03.039
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发表时间：
2019-06-20
期刊：
影响因子：
3.5
通讯作者：
Li, Jia-Da
中科院分区：
文献类型：
--
作者：
Dai, Wenting;Wu, Jiayu;Li, Jia-Da
卡尔曼综合征（KS）的特征是嗅觉丧失和低促性腺激素性性腺功能减退症的相关性。低促性腺激素性性腺功能减退症是由于促性腺激素释放激素（GnRH）的产生、分泌或作用不足所致。最近在 KS 和听力损失患者中发现了转录因子 SOX10 的突变。在这项研究中，我们通过外显子组测序在一组中国 KS 患者中发现了三种新的 SOX10 突变。两种突变（A44G 和 L80V）处于杂合状态，而另一种突变（G41V）是纯合突变。携带G41V纯合突变的患者双耳听力受损，而携带L80V杂合突变的患者左耳听力轻微受损。功能研究表明，所有三种 SOX10 突变均显示出单独反式激活 MITF 启动子或与 PAX3 协同作用的能力降低，尽管它们显示出相似的亚细胞定位和 DNA 结合能力。我们的研究进一步强调了 SOX10 单倍体不足作为 KS 听力问题遗传原因的重要性。
Kallmann syndrome (KS) is characterized by the association of anosmia and hypogonadotropic hypogonadism. The hypogonadotropic hypogonadism is due to deficient production, secretion or action of gonadotropin-releasing hormone (GnRH). Mutations in transcription factor SOX10 have been recently identified in patients with KS and hearing loss. In this study, we identified three novel SOX10 mutations in a cohort of Chinese KS patients by using exome sequencing. Two mutations (A44G and L80V) are in heterozygous state whereas the other one (G41V) is a homozygous mutation. The patient with a homozygous G41V mutation had impaired hearing in both ears, whereas the patient with a heterozygous L80V mutation showed subtle hearing impairment in the left ear. Functional studies indicated that all three SOX10 mutations showed reduced capacity to transactivate the MITF promoter alone or in synergy with PAX3, although they showed similar subcellular localization, and DNA binding ability. Our study further highlighted the significance of SOX10 haploinsufficiency as a genetic cause of KS with hearing problem.