![Putative topology of human pendrin and location of the V239D, G334V X335 and I487Y FSX39 mutations. The 15- transmembrane model, as proposed in [35] shows the position of the mutations V239D, G334V X335 and I487Y FSX39; the amino acids involved in substitutions are indicated in enlarged gray letters.](https://www.researchgate.net/profile/Moien_Kanaan/publication/51829675/figure/fig1/AS:339708128317440@1458004137434/Putative-topology-of-human-pendrin-and-location-of-the-V239D-G334V-X335-and-I487Y-FSX39_Q320.jpg)
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Functional Characterization of Pendrin Mutations Found in the Israeli and Palestinian Populations
Abstract and Figures
Pendrin is a transport protein exchanging chloride for other anions, such as iodide in the thyroid gland or bicarbonate in the inner ear. Mutations in the SLC26A4 gene encoding for pendrin are responsible for both syndromic (Pendred syndrome) and non-syndromic (non-syndromic enlarged vestibular aqueduct, EVA) hearing loss. Besides clinical and radiological assessments, molecular and functional studies are essential for the correct diagnosis of Pendred syndrome and non-syndromic EVA. While a broad spectrum of mutations found in the Caucasian population has been functionally characterized, little is known about mutations specifically occurring in the populations of the Middle East. Here we show the characterization of the ion transport activity of three pendrin mutations previously found in deaf patients with EVA in the Israeli Jewish and Palestinian Arab populations, i.e. V239D, G334V X335 and I487Y FSX39.
Wild type and mutated pendrin allelic variants were functionally characterized in a heterologous over-expression system. The Cl(-)/I(-) and Cl(-)/OH(-) exchange activities were assessed by fluorometric methods suitable for measuring iodide fluxes and the intracellular pH.
Both the Cl(-)/I(-) and the Cl(-)/OH(-) exchange activities of pendrin V239D, G334V X335 and I487Y FSX39 were significantly reduced with respect to the wild type, with V239D displaying a residual iodide transport.
Functional assays confirmed the diagnosis of non-syndromic EVA due to SLC26A4 mutations performed by radiological and molecular tests in deaf patients belonging to the Israeli Jewish and Palestinian Arab populations. The new finding that the V239D mutation displays residual function suggests that the symptoms caused by this mutation could be ameliorated by a pendrin 'activator', if available.
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... The ion transport activity of pendrin was determined by measuring the iodide influx in pendrin-transfected cells by a fluorometric method, as formerly described [24,28,29,[32][33][34][35][36][37][38]. Shortly, cells were seeded into black 96-well plates, grown overnight, and cotransfected with 0.12 µg/well of a plasmid encoding for the iodide-sensitive EYFP variant H148Q;I152L [39] and 0.12 µg/well of a pTARGET plasmid encoding for pendrin. ...
... Cells expressing human or mouse pendrin exhibited a similar fluorescence decrease of approximately 80% over the experimental period, and this decrease was significantly higher compared to that measured in cells expressing no pendrin. This behavior is consistent with the I − /Cl − anion exchange activity of pendrin and is in good agreement with former observations [24,28,29,[32][33][34][35][36][37][38]. Cells expressing human or mouse pendrin p.L117F still exhibited a substantial I − /Cl − anion exchange activity, which was, however, reduced compared to the wild type. ...
The SLC26A4 gene, which encodes the anion exchanger pendrin, is involved in determining
syndromic (Pendred syndrome) and non-syndromic (DFNB4) autosomal recessive hearing loss. SLC26A4 c.349C>T, p.L117F is a relatively common allele in the Ashkenazi Jewish community, where its minor allele frequency is increased compared to other populations. Although segregation and allelic data support the pathogenicity of this variant, former functional tests showed characteristics that were indistinguishable from those of the wild-type protein. Here, we applied a triad of cell-based assays, i.e., measurement of the ion transport activity by a fluorometric method, determination of the subcellular localization by confocal microscopy, and assessment of protein expression levels, to conclusively assign or exclude the pathogenicity of SLC26A4 p.L117F. This protein variant showed a moderate, but significant, reduction in ion transport function, a partial retention in the endoplasmic reticulum, and a strong reduction in expression levels as a consequence of an accelerated degradation by the Ubiquitin Proteasome System, all supporting pathogenicity. The functional and molecular features of human pendrin p.L117F were recapitulated by the mouse ortholog, thus indicating that a mouse carrying this variant might represent a good model of Pendred syndrome/DFNB4.
... Families from regions with traditions of consanguinity have been particularly informative for discovery of genes responsible for recessive traits. In particular, over the past 20 y, families from Palestinian communities with traditions of consanguineous marriages and large families have been instrumental to the discovery and characterization of genes responsible for hearing loss (4)(5)(6)(7)(8)(9)(10)(11). For this project, we characterized the genetics of inherited hearing loss throughout the Palestinian population, ascertaining children with hearing loss throughout the Palestinian West Bank and Gaza and evaluating responsible genes and mutations. ...
... Association analyses have also confirmed that SLC26A4 gene variants are related to SBP and DBP [70]. In functional studies, pendrin P70L, P301L, F667C [71], E29Q, V88I/R409H, G424D, T485R [72], V239D, G334V/X335, I487Y/FSX39 [73], and V510D [74] are found to be the reduction or loss of function variants, whereas pendrin V88I and G740S exhibit a gain of function [71]. To date pendrin variants identified by functional studies have been well summarized in the review of Dossena et al. [75], which pointed out that the involvement of a charged amino acid of pendrin is not always sufficient to induce a detrimental effect on the ion transport such as D266N and K369E. ...
Hypertension affects 30% of adults and is the leading risk factor for cardiovascular disease. Kidney sodium reabsorption plays a vital role in the initial stage and development of essential hypertension. It has been extensively reported that the variants of kidney ion handling genes are associated to blood pressure, and clinical features of hypertension. However, the underlying mechanisms by which these variants alter protein function are rarely summarized. In addition, the variation of one single gene is often limited to induce a significant effect on blood pressure. In the past few decades, the influence by genes × genes (G × G) and/or genotype × environment (G × E) interactions on a given trait, for example blood pressure, have been widely considered, especially in studies on polygenic genetic traits. In this review, we discuss the progress in genetics studies on kidney ion handling genes, encoding Na+ channels (NCC, NKCC2, ENaCs), K+ channel (ROMK), and Cl- channels (Pendrin, CLC-Kb), respectively, and their upstream kinases, WNKs and SGK1. We seek to clarify how these genes are involved in kidney sodium absorption and influence blood pressure, especially emphasizing the underlying mechanisms by which genetic variants alter protein functions and interaction in blood pressure regulation. This review aims to enhance our understanding of the important role of kidney ion handling genes/channels in blood pressure control.
... In this study, two out of the four disease -causing variants reported have been previously described in individuals of Indian ethnic origin: p.Arg409Pro [69,70] and p.Ile490Leu [71]. Other variants found in our study include p.Gly334Val, that has been described chie y in people of Mediterranean origin [72] and p.Phe335Leu which is a common variant reported worldwide [73]. ...
Background: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
Methods: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
Results: Of the 200 participants, 52 (26 %) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
Conclusion: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
... In this study, two out of the four disease -causing variants reported have been previously described in individuals of Indian ethnic origin: p.Arg409Pro [69,70] and p.Ile490Leu [71]. Other variants found in our study include p.Gly334Val, that has been described chie y in people of Mediterranean origin [72] and p.Phe335Leu which is a common variant reported worldwide [73]. ...
Background: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
Methods: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
Results: Of the 200 participants, 52 (26 %) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
Conclusion: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
... By evaluating trafficking of the normal pendrin protein and the mutant one (p.Val239Asp) in living cells using GFP chimeras, Tekin et al. found that the mutant pendrin is retained in the endoplasmic reticulum, whereas the normal one targets the plasma membrane [21]. Moreover, the functional characterization of some SLC26A4 mutations demonstrated that the p. Val239Asp mutant protein has residual activity [25]. This last finding supports the association of c.716T > A (p.Val239Asp) with the DFNB4 form and not the PS one, as previous studies suggested that partial loss of pendrin activity is tolerated by the thyroid and not the ear [16]. ...
Background
The development of next generation sequencing-based techniques showed an important progress in the identification of pathogenic variants related to monogenetic diseases with genetic and phenotypic heterogeneities. Hereditary hearing loss is considered as one of these heterogeneous diseases, given the large number of deafness causing genes, the different modes of inheritance and the phenotypic variabilities associated to the severity, age of onset and/or presence or absence of other clinical manifestations.
Material and methods
In this study, we performed next-generation sequencing (NGS) in 51 UAE patients with hearing loss and no GJB2 mutations. In addition, we reviewed all reported SLC26A4 missense mutations with a confirmed DFNB4/Pendred syndrome phenotype and tried to find a genotype/phenotype correlation using different criteria.
Results
By analyzing the NGS data, we identified one new SLC26A4 variant c.1150G > C (p.Glu384Gln) and one known SLC26A4 mutation c.716T > A (p.Val239Asp) in two different patients. Direct Sanger sequencing and segregation analyses confirmed the implication of both DNA variants in the deafness phenotype. Moreover, the clinical examination of both patients showed that one patient has syndromic deafness (Pendred syndrome) and the second one has non-syndromic deafness. The analysis of all confirmed missense mutations didn't reveal a complete genotype/phenotype correlation.
Conclusion
To the best of our knowledge, this is the first report of mutations associated with DFNB4/Pendred deafness in the GCC region.
... In this study, two out of the four disease -causing variants reported have been previously described in individuals of Indian ethnic origin: p.Arg409Pro [69,70] and p.Ile490Leu [71]. Other variants found in our study include p.Gly334Val, that has been described chie y in people of Mediterranean origin [72] and p.Phe335Leu which is a common variant reported worldwide [73]. ...
Background: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
Methods: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
Results: Of the 200 participants, 52 (26 %) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
Conclusion: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
... In this study, two out of the four disease -causing variants reported have been previously described in individuals of Indian ethnic origin: p.Arg409Pro [69,70] and p.Ile490Leu [71]. Other variants found in our study include p.Gly334Val, that has been described chie y in people of Mediterranean origin [72] and p.Phe335Leu which is a common variant reported worldwide [73]. ...
Background: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
Methods: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
Results: Of the 200 participants, 52 (26 %) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
Conclusion: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
... In this study, two out of the four disease -causing variants reported have been previously described in individuals of Indian ethnic origin: p.Arg409Pro [69,70] and p.Ile490Leu [71]. Other variants found in our study include p.Gly334Val, that has been described chiefly in people of Mediterranean origin [72] and p.Phe335Leu which is a common variant reported worldwide [73]. ...
Background
To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
Methods
After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
Results
Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
Conclusion
A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
... In this study, two out of the four disease -causing variants reported have been previously described in individuals of Indian ethnic origin: p.Arg409Pro [69,70] and p.Ile490Leu [71]. Other variants found in our study include p.Gly334Val, that has been described chie y in people of Mediterranean origin [72] and p.Phe335Leu which is a common variant reported worldwide [73]. ...
Background: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS).
Methods: After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary.
Results: Of the 200 participants, 52 (26 %) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West.
Conclusion: A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.
Pendred syndrome is an autosomal recessive disorder characterized by the association between sensorineural hearing loss and
thyroid swelling or goitre and is likely to be the most common form of syndromic deafness. Within the thyroid gland of affected
individuals, iodide is incompletely organified with variable effects upon thyroid hormone biosynthesis, whilst the molecular
basis of the hearing loss is unknown. The PDSgene has been identified by positional cloning of chromosome 7q31, within the Pendred syndrome critical linkage interval and
encodes for a putative ion transporter called pendrin. We have investigated a cohort of 56 kindreds, all with features suggestive
of a diagnosis of Pendred syndrome. Molecular analysis of the PDSgene identified 47 of the 60 (78%) mutant alleles in 31 families (includes three homozygous consanguineous kindreds and one
extended family segregating three mutant alleles). Moreover, four recurrent mutations accounted for 35 (74%) of PDS disease chromosomes detected and haplotype analysis would favour common founders rather than mutational hotspots within the
PDS gene. Whilst these findings demonstrate molecular heterogeneity for PDS mutations associated with Pendred syndrome, this study would support the use of molecular analysis of the PDS gene in the assessment of families with congenital hearing loss.
Asthma exacerbations can be triggered by viral infections or allergens. The Th2 cytokines IL-13 and IL-4 are produced during allergic responses and cause increases in airway epithelial cell mucus and electrolyte and water secretion into the airway surface liquid (ASL). Since ASL dehydration can cause airway inflammation and obstruction, ion transporters could play a role in pathogenesis of asthma exacerbations. We previously reported that expression of the epithelial cell anion transporter pendrin is markedly increased in response to IL-13. Herein we show that pendrin plays a role in allergic airway disease and in regulation of ASL thickness. Pendrin-deficient mice had less allergen-induced airway hyperreactivity and inflammation than did control mice, although other aspects of the Th2 response were preserved. In cultures of IL-13-stimulated mouse tracheal epithelial cells, pendrin deficiency caused an increase in ASL thickness, suggesting that reductions in allergen-induced hyperreactivity and inflammation in pendrin-deficient mice result from improved ASL hydration. To determine whether pendrin might also play a role in virus-induced exacerbations of asthma, we measured pendrin mRNA expression in human subjects with naturally occurring common colds caused by rhinovirus and found a 4.9-fold increase in mean expression during colds. Studies of cultured human bronchial epithelial cells indicated that this increase could be explained by the combined effects of rhinovirus and IFN-gamma, a Th1 cytokine induced during virus infection. We conclude that pendrin regulates ASL thickness and may be an important contributor to asthma exacerbations induced by viral infections or allergens.
Pendred syndrome (PDS) is an autosomal recessive disorder characterized by congenital deafness, goiter and iodide organification defect. Presence of inner ear malformations is essential for the clinical diagnosis. Most individuals with PDS are clinically and biochemically euthyroid. Mutations in the PDS gene encoding pendrin protein have been shown to be associated with PDS. It has been recently demonstrated that some families with features of PDS do not have the inner ear malformations and mutations in the PDS gene. This condition has been named as “pseudo−Pendred syndrome” (pseudo−PDS), and has been hypothesized to be of autoimmune origin. Here we report four siblings who have goiter, severe hypothyroidism, a positive perchlorate discharge test and sensorineural deafness, but not the inner ear abnormality which is diagnostic for PDS. We suggest that thyroid peroxidase (TPO) gene should be analyzed in pseudo−PDS patients with congenital goitrous hypothyroidism and deafness.
Conflict of interest:None declared.
Mutations of SLC26A4 are among the most prevalent causes of hereditary deafness. Deafness in the corresponding mouse model, Slc26a4(-/-), results from an abnormally enlarged cochlear lumen. The goal of this study was to determine whether the cochlear enlargement originates with defective cochlear fluid transport or with a malfunction of fluid transport in the connected compartments, which are the vestibular labyrinth and the endolymphatic sac. Embryonic inner ears from Slc26a4(+/-) and Slc26a4(-/-) mice were examined by confocal microscopy ex vivo or after 2 days of organ culture. Culture allowed observations of intact, ligated or partially resected inner ears. Cochlear lumen formation was found to begin at the base of the cochlea between embryonic day (E) 13.5 and 14.5. Enlargement was immediately evident in Slc26a4(-/-) compared to Slc26a4(+/-) mice. In Slc26a4(+/-) and Slc26a4(-/-) mice, separation of the cochlea from the vestibular labyrinth by ligation at E14.5 resulted in a reduced cochlear lumen. Resection of the endolymphatic sacs at E14.5 led to an enlarged cochlear lumen in Slc26a4(+/-) mice but caused no further enlargement of the already enlarged cochlear lumen in Slc26a4(-/-) mice. Ligation or resection performed later, at E17.5, did not alter the cochlea lumen. In conclusion, the data suggest that cochlear lumen formation is initiated by fluid secretion in the vestibular labyrinth and temporarily controlled by fluid absorption in the endolymphatic sac. Failure of fluid absorption in the endolymphatic sac due to lack of Slc26a4 expression appears to initiate cochlear enlargement in mice, and possibly humans, lacking functional Slc26a4 expression.
Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and thyroid goiter. The thyroid disease typically develops around puberty and is associated with a mild organification defect, characterized by an inappropriate discharge of iodide upon perchlorate stimulation (a positive perchlorate discharge test). The gene (PDS) mutated in Pendred syndrome is expressed in thyroid and encodes a 780-amino acid protein (pendrin) that has recently been shown to function as an iodide/chloride transporter. We sought to establish the location of pendrin in the thyroid and to examine the regulatory network controlling its synthesis. Using peptide-specific antibodies for immunolocalization studies, pendrin was detected in a limited subset of cells within the thyroid follicles, exclusively at the apical membrane of the follicular epithelium. Interestingly, significantly greater amounts of pendrin were encountered in thyroid tissue from patients with Graves’ disease. Using a cultured rat thyroid cell line (FRTL-5), PDS expression was found to be significantly induced by low concentrations of thyroglobulin (TG),but not by TSH, sodium iodide, or insulin. This is different fromthe established effect of TG, more typically a potent suppressor of thyroid-specific gene expression. Together, these results suggest that pendrin is an apical porter of iodide in the thyroid and that the expression and function of both the apical and basal iodide porters are coordinately regulated by follicular TG.
Enlargement of the vestibular aqueduct (EVA) is one of the most common inner ear malformations associated with sensorineural hearing loss in children. The delayed onset and progressive nature of this phenotype offer a window of opportunity to prevent or retard progression of hearing loss. EVA is not the direct cause of hearing loss in these patients, but rather is a radiologic marker for some underlying pathogenetic defect. Mutations of the SLC26A4 gene are a common cause of EVA. Studies of an Slc26a4 knockout mouse demonstrate that acidification and enlargement of the scala media are early events in the pathogenesis of deafness. The enlargement is driven by fluid secretion in the vestibular labyrinth and a failure of fluid absorption in the embryonic endolymphatic sac. Elucidating the mechanism of hearing loss may offer clues to potential therapeutic strategies.
Renal intercalated cells mediate the secretion or the absorption of OH-/H+ equivalents and Cl- in the distal convoluted tubule (DCT), the connecting tubule (CNT) and the cortical collecting duct (CCD). In so doing, they regulate acid-base balance, vascular volume and blood pressure. In type B and non-A, non-B intercalated cells, Cl- absorption and HCO3- secretion are accomplished through the apical Na+-independent Cl-/HCO3- exchanger, pendrin. With increased circulating aldosterone or angiotensin II, pendrin abundance and function are up-regulated. In the absence of pendrin (Slc26a4 (-/-) or pendrin null mice), aldosterone- and angiotensin II-stimulated Cl- absorption are reduced, which attenuates the blood pressure response to these hormones. Pendrin also modulates aldosterone-induced changes in ENaC abundance and function through a kidney-specific mechanism that does not involve changes in the concentration of a circulating hormone. Instead, pendrin changes ENaC abundance and function, at least in part, by altering luminal HCO3-. Thus, aldosterone and angiotensin II modulate the renal regulation of blood pressure, in part, by regulating pendrin-mediated Cl- absorption and ENaC-mediated Na+ absorption. This review summarizes the contribution of the Cl-/HCO3- exchanger, pendrin, in the renal regulation of blood pressure.