Functional Characterization of Wild-Type and a Mutated Form of SLC26A4 Identified in a Patient with Pendred Syndrome

Dossena, Silvia; Vezzoli, Valeria; Cerutti, Nadia; Bazzini, Claudia; Tosco, M.; Sironi, Chiara; Rodighiero, Simona; Meyer, Gerd; Fascio, Umberto; Fürst, Johannes; Ritter, Markus; Fugazzola, Laura; Persani, Luca; Zorowka, Patrick; Storelli, Carlo; Beck‐Peccoz, Paolo; Botta, Guido Fernando; Paulmichl, Markus

doi:10.1159/000094137

Cited by 38 publications

(57 citation statements)

References 56 publications

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“…Consistent with a recent study (40), we found that niflumic acid, which can inhibit pendrin activity (37), only partially inhibited anion transport and mucus production induced by anion transporters including pendrin (Fig. 6).…”

Section: Discussionsupporting

confidence: 92%

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Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Nakao¹,

Kanaji²,

Ohta³

et al. 2008

The Journal of Immunology

120

148

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Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD.

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Section: Discussionsupporting

confidence: 92%

“…Niflumic acid, a well-known blocker of anion transporters, has recently been shown to act as an inhibitor of pendrin (37). We thus investigated whether niflumic acid inhibits anion transport by pendrin, followed by attenuated mucus production (Fig.…”

Section: Effects Of Niflumic Acid On Mucus Production By Pendrinmentioning

confidence: 99%

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Nakao¹,

Kanaji²,

Ohta³

et al. 2008

The Journal of Immunology

120

148

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“…In yet another study performed by Taylor et al (27) on PS/ns-EVA patients, three mutations of the same type (G672E, G102R, and Q446R) were described, and all showed a loss of functionality. We recently described a mutation, S28R, which again, reduced functionality (14,19). Another mutation, R409H, in which a Table S1.…”

Section: Discussionmentioning

confidence: 99%

“…SLC26A4 Site-Directed Mutagenesis. The site-directed mutagenesis of SLC26A4 was done as described in detail in (14), and in SI Materials and Methods.…”

Section: Subjectsmentioning

confidence: 99%

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Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Pera

Dossena

Rodighiero³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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104

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Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests.ion transport physiology ͉ genotype-phenotype correlation P endred syndrome (PS) (OMIM#274600) (1) is an autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) (2) to Mondini malformation (3), combined with deficient iodide organification in the thyroid gland, as demonstrated by the positive perchlorate discharge test in affected individuals (4-7). Another form of SNHL associated with EVA, however, showing normal thyroid function, is called nonsyndromic EVA (ns-EVA) (OMIM#600791). The clinical features of PS are the consequence of impaired pendrin function (1), a protein encoded by the SLC26A4 gene (NM 000441). It is a member of the multifunctional anion transporter family SLC26, which mediates the exchange of anions including Cl Ϫ , HCO 3 Ϫ , OH Ϫ , I Ϫ , or formate (8). Pendrin seems to be responsible for the efflux of iodide in thyrocytes (9-11), and for mediating Cl Ϫ /HCO 3 Ϫ exchange in the kidney cortex (12) and inner ear. In the latter, pendrin is involved in the conditioning of endolymphatic fluid, presumably because of HCO 3 Ϫ secretion (13), thereby modifying inner ear acid-base homeostasis. A variable feature of PS is the development of goitre (apparent in only about 50% of the affected individuals). At the thyroid level, the role of pendrin is not conclusive. The transporter could act as an iodide transporter at the apical membrane of thyroid cells and impaired function could therefore lead to the iodide organification defect observed in PS patients (10,11,(14)(15)(16). PS seems to be linked to bi-allelic mutations of the SLC26A4 genes. ns-EVA is genetically more heterogeneous relative to PS, and a...

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Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss

et al. 2018

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Due to the high genetic heterogeneity of hearing loss, current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of hearing loss. As one of its major tasks, our Expert Panel has adapted the ACMG/AMP guidelines for the interpretation of sequence variants in hearing loss genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP hearing loss rules. Three rules remained unchanged, four rules were removed, and the remaining twenty-one rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and expert opinion. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These hearing loss-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with hearing loss.

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Functional Characterization of Wild-Type and a Mutated Form of SLC26A4 Identified in a Patient with Pendred Syndrome

Cited by 38 publications

References 56 publications

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Identification of Pendrin as a Common Mediator for Mucus Production in Bronchial Asthma and Chronic Obstructive Pulmonary Disease

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss

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