Transcriptional control of SLC26A4 is involved in pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4)
Transcriptional control of SLC26A4 is involved in pendred syndrome and nonsyndromic enlargement of vestibular aqueduct (DFNB4)
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DOI：
10.1086/518314
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发表时间：
2007-06-01
影响因子：
9.8
通讯作者：
Smith, Richard J. H.
中科院分区：
文献类型：
--
作者：
Yang, Tao;Vidarsson, Hilmar;Smith, Richard J. H.
虽然已知阴离子转运基因SLC26A4的隐性突变是导致Pendred综合征（PS）和与前庭导尿管增大（EVA）相关的非综合征性听力损失（也称为“DFNB4”）的原因，但这种表型的大部分患者在一个或两个等位基因的SLC26A4编码区缺乏突变。我们已经确定并表征了SLC26A4启动子中一个关键的转录调控元件，该元件与SLC26A4的转录激活因子FOX11结合。在9例PS或非综合征性EVA患者中，该调控元件的C - 103T -> C突变干扰FOXI1结合并完全消除FOXI1介导的转录激活。我们还鉴定了6例fox1突变患者，这些突变损害了其激活SLC26A4转录的能力。在一个家庭中，在携带SLC26A4和FOXI1单突变的受影响个体中，EVA表型以双杂合模式分离。这一发现与我们的观察一致，EVA发生在Slc26a4(+/-)；fox1（+/-）双杂合小鼠突变体。这些结果支持PS和非综合征性EVA分子发病机制的一种新的剂量依赖模型，该模型涉及SLC26A4及其转录调控机制。
Although recessive mutations in the anion transporter gene SLC26A4 are known to be responsible for Pendred syndrome (PS) and nonsyndromic hearing loss associated with enlarged vestibular aqueduct (EVA), also known as "DFNB4," a large percentage of patients with this phenotype lack mutations in the SLC26A4 coding region in one or both alleles. We have identified and characterized a key transcriptional regulatory element in the SLC26A4 promoter that binds FOX11, a transcriptional activator of SLC26A4. In nine patients with PS or nonsyndromic EVA, a novel c.- 103T -> C mutation in this regulatory element interferes with FOXI1 binding and completely abolishes FOXI1-mediated transcriptional activation. We have also identified six patients with mutations in FOXI1 that compromise its ability to activate SLC26A4 transcription. In one family, the EVA phenotype segregates in a double-heterozygous mode in the affected individual who carries single mutations in both SLC26A4 and FOXI1. This finding is consistent with our observation that EVA occurs in the Slc26a4(+/-); Foxi1(+/-) double-heterozygous mouse mutant. These results support a novel dosage-dependent model for the molecular pathogenesis of PS and nonsyndromic EVA that involves SLC26A4 and its transcriptional regulatory machinery.