Dossena Silvia, Nofziger Charity, Tamma Grazia, Bernardinelli Emanuele, Vanoni Simone, Nowak Christoph, Grabmayer Elisabeth, Kössler Sonja, Stephan Susanne, Patsch Wolfgang, Paulmichl Markus
Institute of Pharmacology and Toxicology, Paracelsus Medical University, Salzburg, Austria.
Cell Physiol Biochem. 2011;28(3):451-66. doi: 10.1159/000335107. Epub 2011 Nov 18.
Pendrin (SLC26A4, PDS) is an electroneutral anion exchanger transporting I(-), Cl(-), HCO(3)(-), OH(-), SCN(-) and formate. In the thyroid, pendrin is expressed at the apical membrane of the follicular epithelium and may be involved in mediating apical iodide efflux into the follicle; in the inner ear, it plays a crucial role in the conditioning of the pH and ion composition of the endolymph; in the kidney, it may exert a role in pH homeostasis and regulation of blood pressure. Mutations of the pendrin gene can lead to syndromic and non-syndromic hearing loss with EVA (enlarged vestibular aqueduct). Functional tests of mutated pendrin allelic variants found in patients with Pendred syndrome or non-syndromic EVA (ns-EVA) revealed that the pathological phenotype is due to the reduction or loss of function of the ion transport activity. The diagnosis of Pendred syndrome and ns-EVA can be difficult because of the presence of phenocopies of Pendred syndrome and benign polymorphisms occurring in the general population. As a consequence, defining whether or not an allelic variant is pathogenic is crucial. Recently, we found that the two parameters used so far to assess the pathogenic potential of a mutation, i.e. low incidence in the control population, and substitution of evolutionary conserved amino acids, are not always reliable for predicting the functionality of pendrin allelic variants; actually, we identified mutations occurring with the same frequency in the cohort of hearing impaired patients and in the control group of normal hearing individuals. Moreover, we identified functional polymorphisms affecting highly conserved amino acids. As a general rule however, we observed a complete loss of function for all truncations and amino acid substitutions involving a proline. In this view, clinical and radiological studies should be combined with genetic and molecular studies for a definitive diagnosis. In performing genetic studies, the possibility that the mutation could affect regions other than the pendrin coding region, such as its promoter region and/or the coding regions of functionally related genes (FOXI1, KCNJ10), should be taken into account. The presence of benign polymorphisms in the population suggests that genetic studies should be corroborated by functional studies; in this context, the existence of hypo-functional variants and possible differences between the I(-)/Cl(-) and Cl(-)/HCO(3)(-) exchange activities should be carefully evaluated.
Pendrin（SLC26A4，PDS）是一种电中性阴离子交换体，可转运碘离子（I⁻）、氯离子（Cl⁻）、碳酸氢根离子（HCO₃⁻）、氢氧根离子（OH⁻）、硫氰酸根离子（SCN⁻）和甲酸根离子。在甲状腺中，Pendrin表达于滤泡上皮细胞的顶端膜，可能参与介导顶端碘离子向滤泡内的流出；在内耳中，它在内淋巴的pH值调节和离子组成调节中起关键作用；在肾脏中，它可能在pH值稳态和血压调节中发挥作用。Pendrin基因突变可导致伴有前庭导水管扩大（EVA）的综合征型和非综合征型听力损失。对患有 Pendred 综合征或非综合征型 EVA（ns-EVA）患者中发现的 Pendrin 基因突变等位基因变体进行功能测试表明，病理表型是由于离子转运活性的功能降低或丧失所致。由于 Pendred 综合征的表型模拟以及普通人群中存在良性多态性，Pendred 综合征和 ns-EVA 的诊断可能会很困难。因此，确定一个等位基因变体是否具有致病性至关重要。最近，我们发现，迄今为止用于评估突变致病潜力的两个参数，即对照人群中的低发生率以及进化保守氨基酸的替换，并不总是能够可靠地预测 Pendrin 等位基因变体的功能；实际上，我们在听力受损患者队列和正常听力个体对照组中发现了频率相同的突变。此外，我们还鉴定出了影响高度保守氨基酸的功能多态性。然而，一般来说，我们观察到所有涉及脯氨酸的截断和氨基酸替换都会导致功能完全丧失。因此，临床和放射学研究应与遗传和分子研究相结合以做出明确诊断。在进行遗传研究时，应考虑到突变可能影响 Pendrin 编码区以外的区域，例如其启动子区域和/或功能相关基因（FOXI1、KCNJ10）的编码区。人群中存在良性多态性表明遗传研究应通过功能研究来佐证；在这种情况下，应仔细评估功能低下变体的存在以及 I⁻/Cl⁻和 Cl⁻/HCO₃⁻交换活性之间可能存在的差异。
