Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome
Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome
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DOI：
10.1086/513322
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发表时间：
2007-04-01
影响因子：
9.8
通讯作者：
Hildebrandt, Friedhelm
中科院分区：
文献类型：
--
作者：
Hoskins, Bethan E.;Cramer, Carl H., II;Hildebrandt, Friedhelm
鳃裂-耳-肾综合征（BOR）是一种常染色体显性发育障碍，以鳃裂弓缺陷、听力损失和肾脏异常为特征。已知EYA1突变可引起BOR。最近，与EYA1相互作用的SIX1突变被确定为BOR的另一个原因。6蛋白家族的另一个成员unc-39 （SIX5）也被报道在秀丽隐杆线虫中直接与yya -1相互作用。我们假设这种相互作用在人类中是保守的，并且EYA1的相互作用基因代表了BOR的良好候选基因。因此，我们筛选了95名BOR患者的SIX5突变队列。在5个个体中鉴定出4种不同的杂合错义突变。这些突变的功能分析表明，两个突变影响了EYA1-SIX5的结合以及SIX5或EYA1-SIX5复合物激活基因转录的能力。因此，我们确定了SIX5的杂合突变是BOR的新原因。
Branchio-oto-renal syndrome (BOR) is an autosomal dominant developmental disorder characterized by the association of branchial arch defects, hearing loss, and renal anomalies. Mutations in EYA1 are known to cause BOR. More recently, mutations in SIX1, which interacts with EYA1, were identified as an additional cause of BOR. A second member of the SIX family of proteins, unc-39 (SIX5), has also been reported to directly interact with eya-1 in Caenorhabditis elegans. We hypothesized that this interaction would be conserved in humans and that interactors of EYA1 represent good candidate genes for BOR. We therefore screened a cohort of 95 patients with BOR for mutations in SIX5. Four different heterozygous missense mutations were identified in five individuals. Functional analyses of these mutations demonstrated that two mutations affect EYA1-SIX5 binding and the ability of SIX5 or the EYA1-SIX5 complex to activate gene transcription. We thereby identified heterozygous mutations in SIX5 as a novel cause of BOR.