Pendrin (SLC26A4, PDS) is an electroneutral anion exchanger transporting I ^-, Cl ^-, HCO₃^-, 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 ^-/HCO₃^- exchange activities should be carefully evaluated.

Background: 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.

Background: The operon structure of the C. elegans genome was used to identify functional interaction partners for the chloride channel ICln.Results: Human ICln and HSPC038 functionally interact, and this interaction between the two proteins was also identified on a molecular level.Conclusion: The functional interaction between ICln and HSPC038 modulates the regulation of the cellular volume.Significance: The operon structure of the C. elegans genome can be used to identify unknown interaction partners including those of membrane proteins, and the summarized experiments provide further insight into the interactome of the connector hub ICln.