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首页> 外文期刊>Cellular Physiology and Biochemistry >Identification of allelic variants of pendrin (SLC26A4) with loss and gain of function
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Identification of allelic variants of pendrin (SLC26A4) with loss and gain of function

机译：鉴定功能缺失和功能增强的Pendrin（SLC26A4）等位基因变体

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Pendrin is a multifunctional anion transporter that exchanges chloride and iodide in the thyroid, as well as chloride and bicarbonate in the inner ear, kidney and airways. Loss or reduction in the function of pendrin results in both syndromic (Pendred syndrome) and non-syndromic (non-syndromic enlarged vestibular aqueduct (ns-EVA)) hearing loss. Factors inducing an up-regulation of pendrin in the kidney and the lung may have an impact on the pathogenesis of hypertension, chronic obstructive pulmonary disease (COPD) and asthma. Here we characterize the ion transport activity of wild-type (WT) pendrin and seven of its allelic variants selected among those reported in the single nucleotide polymorphisms data base (dbSNPs), some of which were previously identified in a cohort of individuals with normal hearing or deaf patients belonging to the Spanish population. Methods: WT and mutated pendrin allelic variants were functionally characterized in a heterologous over-expression system by means of fluorometric methods evaluating the I ~-/Cl~- and Cl~-/OH~- exchange and an assay evaluating the efflux of radiolabeled iodide. Results: The transport activity of pendrin P70L, P301L and F667C is completely abolished; pendrin V609G and D687Y allelic variants are functionally impaired but retain significant transport. Pendrin F354S activity is indistinguishable from WT, while pendrin V88I and G740S exhibit a gain of function. Conclusion: Amino acid substitutions involving a proline always result in a severe loss of function of pendrin. Two hyperfunctional allelic variants (V88I, G740S) have been identified, and they may have a contributing role in the pathogenesis of hypertension, COPD and asthma.
机译：Pendrin是一种多功能阴离子转运蛋白，可交换甲状腺中的氯离子和碘离子，以及内耳，肾脏和气道中的氯离子和碳酸氢根离子。 Pendrin功能的丧失或减少会导致综合症（Pendred综合征）和非综合症（非综合症前庭导水管（ns-EVA））听力损失。导致肾和肺中Pendrin上调的因素可能会影响高血压，慢性阻塞性肺疾病（COPD）和哮喘的发病机理。在这里，我们描述了野生型（WT）Pendrin及其七个等位基因变体的离子迁移活性，这些变体选自单核苷酸多态性数据库（dbSNPs）中报道的那些，其中一些先前已在一群听力正常的人群中鉴定出或属于西班牙人口的聋人患者。方法：通过荧光方法评估I〜-/ Cl〜-和Cl〜-/ OH〜-交换，并通过测定放射性标记碘化物流出的试验，在异源过表达系统中对WT和突变的Pendrin等位基因变体进行功能表征。结果：Pendrin P70L，P301L和F667C的转运活性被完全消除; pendrin V609G和D687Y等位基因变体功能受损，但保留大量转运。 Pendrin F354S的活性与WT并无区别，而pendrin V88I和G740S则显示出功能增强。结论：涉及脯氨酸的氨基酸取代总是导致Pendrin功能严重丧失。已鉴定出两个功能亢进的等位基因变体（V88I，G740S），它们可能在高血压，COPD和哮喘的发病机理中起重要作用。

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