Characterization of SLC26A9 in Patients with CF-Like Lung Disease
Characterization of SLC26A9 in Patients with CF-Like Lung Disease
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DOI：
10.1002/humu.22382
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发表时间：
2013-10-01
期刊：
影响因子：
3.9
通讯作者：
Sermet-Gaudelus, Isabelle
中科院分区：
文献类型：
--
作者：
Bakouh, Naziha;Bienvenu, Thierry;Sermet-Gaudelus, Isabelle
弥漫性支气管扩张是呼吸科门诊常见的问题。我们假设溶质载体26 A9（SLC 26 A9）基因（编码主要在肺中表达的氯离子（Cl-）转运蛋白）的突变可能导致粘膜纤毛清除缺陷。我们描述了弥漫性特发性支气管扩张症杂合子患者SLC 26 A9基因中的两种错义变体：p.Arg575Trp，在CFTR基因中也为p.Phe508del杂合子的患者中鉴定;和p.Val486Ile。这两种突变体在非洲爪蟾卵母细胞中的表达废除了SLC 26 A9介导的Cl-电导，而不降低蛋白质膜表达。CFTR与SLC 26 A9-p.Val486Ile的共表达导致PKA刺激诱导的Cl-电流显著增加，与表达CFTR和SLC 26 A9-WT的卵母细胞中获得的结果相似。相反，CFTR与SLC 26 A9-p.Arg575Trp的共表达抑制了SLC 26 A9增强的CFTR对PKA的活化。进一步的结构-功能分析使我们提出了一个包含SLC 26 A9-STAS结构域中Arg 575的位点，用于CFTR-SLC 26 A9相互作用。我们假设SLC 26 A9-p.Arg575Trp通过改变SLC 26 A9-CFTR相互作用来阻止SLC 26 A9介导的CFTR功能性激活。虽然我们不能证实这些突变本身是有害的，我们建议，他们触发一个单一的CFTR突变的致病作用，并提供洞察到一个新的机制，Cl-转运改变整个呼吸道粘膜，CFTR的功能抑制的基础上。(C)2013 Wiley Periodicals，Inc.
Diffuse bronchiectasis is a common problem in respiratory clinics. We hypothesized that mutations in the solute carrier 26A9 (SLC26A9) gene, encoding for a chloride (Cl-) transporter mainly expressed in lungs, may lead to defects in mucociliary clearance. We describe two missense variants in the SLC26A9 gene in heterozygote patients presenting with diffuse idiopathic bronchiectasis : p.Arg575Trp, identified in a patient also heterozygote for p.Phe508del in the CFTR gene; and p.Val486Ile. Expression of both mutants in Xenopus laevis oocytes abolished SLC26A9-mediated Cl- conductance without decreasing protein membrane expression. Coexpression of CFTR with SLC26A9-p.Val486Ile resulted in a significant increase in the Cl- current induced by PKA stimulation, similar to that obtained in oocytes expressing CFTR and SLC26A9-WT. In contrast, coexpression of CFTR with SLC26A9-p.Arg575Trp inhibited SLC26A9-enhanced CFTR activation upon PKA. Further structure-function analyses led us to propose a site encompassing Arg575 in the SLC26A9-STAS domain for CFTR-SLC26A9 interaction. We hypothesize that SLC26A9-p.Arg575Trp prevented SLC26A9-mediated functional activation of CFTR by altering SLC26A9-CFTR interaction. Although we cannot confirm that these mutations by themselves are deleterious, we propose that they trigger the pathogenic role of a single CFTR mutation and provide insight into a novel mechanism of Cl- transport alteration across the respiratory mucosa, based on functional inhibition of CFTR. (C) 2013 Wiley Periodicals, Inc.