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Molecular and functional characterization of human pendrin and its allelic variants

机译：人Pendrin及其等位基因变体的分子和功能表征

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摘要

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.
机译：Pendrin（SLC26A4，PDS）是一种电子中性阴离子交换剂，可转运I〜-，Cl〜-，HCO_3〜-，OH〜-，SCN〜-和甲酸酯。在甲状腺中，pendrin在滤泡上皮的顶膜表达，并可能参与介导碘离子向滤泡的外排;在内耳中，它在调节内淋巴的pH和离子组成方面起着至关重要的作用。在肾脏中，它可能在pH稳态和血压调节中发挥作用。 Pendrin基因的突变可导致EVA（前庭导水管增大）导致综合征和非综合征性听力损失。在Pendred综合征或非综合征性EVA（ns-EVA）患者中发现的突变的pendrin等位基因变体的功能测试表明，病理表型是由于离子转运活性功能的降低或丧失所致。由于存在Pendred综合征的表型和良性多态性，Pendred综合征和ns-EVA的诊断可能很困难。结果，确定等位基因变体是否是致病性至关重要。最近，我们发现，到目前为止，用于评估突变的致病潜力的两个参数，即对照人群中的低发生率和进化保守氨基酸的替代，并不总是可靠地预测pendrin等位基因变体的功能;实际上，我们确定了在听力受损患者队列和正常听力个体的对照组中以相同频率发生的突变。此外，我们确定了影响高度保守氨基酸的功能性多态性。但是，作为一般规则，我们观察到涉及脯氨酸的所有截短和氨基酸取代均完全丧失功能。根据这种观点，临床和放射学研究应与遗传和分子研究相结合，以进行明确的诊断。在进行遗传研究时，应考虑突变可能影响除Pendrin编码区以外的区域的可能性，例如其启动子区和/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，基因研究应得到功能研究的证实。在这种情况下，应仔细评估低功能变体的存在以及I〜-/ Cl〜-和Cl〜-/ HCO_3〜-交换活性之间可能存在的差异。

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