Hoskins Bethan E, Cramer Carl H, Silvius Derek, Zou Dan, Raymond Richard M, Orten Dana J, Kimberling William J, Smith Richard J H, Weil Dominique, Petit Christine, Otto Edgar A, Xu Pin-Xian, Hildebrandt Friedhelm
Department of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
Am J Hum Genet. 2007 Apr;80(4):800-4. doi: 10.1086/513322. Epub 2007 Feb 22.
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.
鳃耳肾综合征（BOR）是一种常染色体显性发育障碍疾病，其特征为鳃弓缺陷、听力丧失和肾脏异常同时出现。已知EYA1基因的突变会导致BOR。最近，与EYA1相互作用的SIX1基因的突变被确定为BOR的另一个病因。据报道，SIX蛋白家族的第二个成员unc-39（SIX5）在秀丽隐杆线虫中也能直接与eya-1相互作用。我们推测这种相互作用在人类中是保守的，并且EYA1的相互作用分子是BOR的良好候选基因。因此，我们对95名BOR患者进行了SIX5基因突变筛查。在5名个体中发现了4种不同的杂合错义突变。对这些突变的功能分析表明，其中两种突变影响EYA1-SIX5的结合以及SIX5或EYA1-SIX5复合物激活基因转录的能力。由此，我们确定SIX5基因的杂合突变是BOR的一个新病因。
