Functional characterization of wild-type and mutated pendrin (SLC26A4), the anion transporter involved in Pendred syndrome

Dossena, Silvia; Rodighiero, Simona; Vezzoli, Valeria; Nofziger, Charity; Salvioni, Elisabetta; Boccazzi, Marta; Grabmayer, Elisabeth; Botta, Guido Fernando; Meyer, Gerd; Fugazzola, Laura; Beck‐Peccoz, Paolo; Paulmichl, Markus

doi:10.1677/jme-08-0175

Cited by 81 publications

(67 citation statements)

References 60 publications

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“…1A). Several topology models for pendrin have been suggested in the literature, although the number of potential transmembrane domains remains ambiguous (28). According to our prediction, Ser-408 is buried in a hydrophobic signature of pendrin within the ninth transmembrane domain (Fig.…”

Section: Slc26a4 Mutation Leads To Deafness and Severe Balance Defects-mentioning

confidence: 51%

“…Fluorometric Analyses-The fluorometric method was described previously in detail (25,(27)(28)(29). Briefly, to evaluate pendrin-induced ion transport, HEK 293 Phoenix cells were transfected with plasmids encoding for human or mouse WT PDS and EYFP, human or mouse PDS S408F and EYFP, or with the empty plasmid encoding for EYFP only.…”

Section: Cloning Of Human and Mouse Pendrin (Pds) And The Respective mentioning

confidence: 99%

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Calcium Oxalate Stone Formation in the Inner Ear as a Result of an Slc26a4 Mutation

Dror

Politi

Shahin

et al. 2010

Journal of Biological Chemistry

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Calcium oxalate stone formation occurs under pathological conditions and accounts for more than 80% of all types of kidney stones. In the current study, we show for the first time that calcium oxalate stones are formed in the mouse inner ear of a genetic model for hearing loss and vestibular dysfunction in humans. The vestibular system within the inner ear is dependent on extracellular tiny calcium carbonate minerals for proper function. Thousands of these biominerals, known as otoconia, are associated with the utricle and saccule sensory maculae and are vital for mechanical stimulation of the sensory hair cells. We show that a missense mutation within the Slc26a4 gene abolishes the transport activity of its encoded protein, pendrin. As a consequence, dramatic changes in mineral composition, size, and shape occur within the utricle and saccule in a differential manner. Although abnormal giant carbonate minerals reside in the utricle at all ages, in the saccule, a gradual change in mineral composition leads to a formation of calcium oxalate in adult mice. By combining imaging and spectroscopy tools, we determined the profile of mineral composition and morphology at different time points. We propose a novel mechanism for the accumulation and aggregation of oxalate crystals in the inner ear.Biomineralization processes in the human body normally occur in a variety of different tissues, including bones, teeth, and otoconia within the vestibular system of the inner ear. The vestibular system is comprised of five sensory organs. Three cristae connected to semicircular canals are sensitive for angular movement, and the saccule and utricle are sensitive for linear acceleration and gravity. Otoconia are small highly dense calcitic minerals that associate exclusively with the saccule and utricle. Thousands of otoconia, partially embedded in a gelatinous matrix, are supported on the sensory epithelium and serve as an inertial mass that is critical for mechanical stimulation (1, 2) Movement of the otoconial layer through action of gravitational or inertial forces activate the underlying mechanosensory hair cells to generate action potentials that are transmitted to the brain.The biomineralization process, such as in otoconia formation, involves organic and inorganic components and results in biominerals that differ significantly in morphology and mechanical properties from similar synthetic or geological minerals (3, 4). Otoconia formation occurs outside the cells and therefore depends on secretion of the required assembly components into the endolymphatic spaces (5). Otoconia seeding in mice begins as early as embryonic day (E)14.5 4 and initiates extensive mineral growth, with the highest rate of calcification at E15-16 (6). By postnatal day (P)7, otoconia achieve their final size and are maintained at progressive ages with a low rate of calcium turnover (7). The main inorganic fraction of otoconia in birds and mammals is calcite (CaCO 3 ), a polymorph of calcium carbonate (2,8). The organic fraction of otoconia contains s...

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Section: Slc26a4 Mutation Leads To Deafness and Severe Balance Defects-mentioning

confidence: 51%

Section: Cloning Of Human and Mouse Pendrin (Pds) And The Respective mentioning

confidence: 99%

Calcium Oxalate Stone Formation in the Inner Ear as a Result of an Slc26a4 Mutation

Dror

Politi

Shahin

et al. 2010

Journal of Biological Chemistry

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“…Most of the current topological models of the SLC26A sequences, including mammalian prestin, feature a SulpTP core domain comprising of 10 or 12 TM regions (Oliver et al, 2001;Dallos and Fakler, 2002;Mount and Romero, 2004;Navaratnam et al, 2005;Dossena et al, 2009). In these models, the MESH motif is outside of the predicted a-helical hydrophobic TM spanning regions and is within a predicted hydrophilic loop.…”

Section: Discussionmentioning

confidence: 99%

A motif of eleven amino acids is a structural adaptation that facilitates motor capability of eutherian prestin

Tan

Pecka

Tang

et al. 2012

Journal of Cell Science

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SummaryCochlear outer hair cells (OHCs) alter their length in response to transmembrane voltage changes. This so-called electromotility is the result of conformational changes of membrane-bound prestin. Prestin-based OHC motility is thought to be responsible for cochlear amplification, which contributes to the exquisite frequency selectivity and sensitivity of mammalian hearing. Prestin belongs to an anion transporter family, the solute carrier protein 26A (SLC26A). Prestin is unique in this family in that it functions as a voltage-dependent motor protein manifested by two hallmarks, nonlinear capacitance and motility. Evidence suggests that prestin orthologs from zebrafish and chicken are anion exchangers or transporters with no motor function. We identified a segment of 11 amino acid residues in eutherian prestin that is extremely conserved among eutherian species but highly variable among non-mammalian orthologs and SLC26A paralogs. To determine whether this sequence represents a motif that facilitates motor function in eutherian prestin, we utilized a chimeric approach by swapping corresponding residues from the zebrafish and chicken with those of gerbil. Motility and nonlinear capacitance were measured from chimeric prestin-transfected human embryonic kidney 293 cells using a voltage-clamp technique and photodiode-based displacement measurement system. We observed a gain of motor function with both of the hallmarks in the chimeric prestin without loss of transport function. Our results show, for the first time, that the substitution of a span of 11 amino acid residues confers the electrogenic anion transporters of zebrafish and chicken prestins with motor-like function. Thus, this motif represents the structural adaptation that assists gain of motor function in eutherian prestin.

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“…The real structure of pendrin has not been defined yet; on the basis of protein structure prediction programs, two models have been proposed for pendrin protein: 12TM and 15TM models. 53,54 This ion transporter also exchanges other anions such as HCO À , OH À , I À or formate. 55 Variations in this gene, as a second prevalent cause of HL, can contribute to both syndromic (Pendred syndrome, PS) and ARNSHL (DFNB4).…”

Section: Genetic Causes Of Nshl In Iran N Mahdieh Et Almentioning

confidence: 99%

Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

et al. 2010

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Hearing loss (HL) is the most prevalent sensory defect affecting 1 in 500 neonates. Genetic factors are involved in half of the cases. The extreme heterogeneity of HL makes it difficult to analyze and determine the accurate genetic causes of the impairment. Up to now, 10 genes, namely, GJB2, GJB6, SLC26A4, TECTA, PJVK, Col11A2, Myo15A, TMC1, RDX and microRNA (miR-183), have been studied in an Iranian population. The prevalence of HL in Iran was estimated to be 2-3 times higher than that in other parts of the world. Here, the most common bases of congenital nonsyndromic hearing loss (NSHL) are discussed. We reviewed GJB2, GJB6 (large deletion), TECTA, SLC26A4 and PEJVK mutations, and studied their frequencies and distributions in different ethnic groups in 1934, 500, 121, 80 and 34 unrelated families throughout Iran, respectively. GJB2 mutation was the most common factor causing NSHL, with a mean frequency of 18.17% in the Iranian population. The importance of Iran's geographical location in the migration pathway from west to east through the silk route was also highlighted. SLC26A4 and TECTA mutations were the second and third main reasons of HL and accounted for up to 10 and 4% of prelingual HL in Iran, respectively. Mutations in GJB2, SLC26, TECTA and PJVK genes have an important role in HL in Iran and a screening test should be generated for better intervention and diagnosis programs.

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Functional characterization of wild-type and mutated pendrin (SLC26A4), the anion transporter involved in Pendred syndrome

Cited by 81 publications

References 60 publications

Calcium Oxalate Stone Formation in the Inner Ear as a Result of an Slc26a4 Mutation

Calcium Oxalate Stone Formation in the Inner Ear as a Result of an Slc26a4 Mutation

A motif of eleven amino acids is a structural adaptation that facilitates motor capability of eutherian prestin

Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

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