The Pendrin Polypeptide

Dossena, Silvia; Bernardinelli, Emanuele; Sharma, Alok; Alper, Seth L.; Paulmichl, Markus

doi:10.1007/978-3-319-43287-8_11

Cited by 5 publications

(6 citation statements)

References 114 publications

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“…Leucine (Leu) and Phenylalanine (Phe) are both neutral non-polar amino acids; however, the structural characteristics of the side chain, which is aliphatic for Leu and aromatic for Phe, appear different. This missense occurs in a residue that is completely conserved among pendrin orthologues from H. sapiens to D. rerio and highly conserved among paralogues ( Figure 6 ) and, according to our structural model, falls within the second transmembrane helix of pendrin [ 45 ]. Therefore, it appeared surprising to us that the amino acid substitution did not affect the protein subcellular distribution and function.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Features of SLC26A4 Common Variant p.L117F

Matulevičius

Bernardinelli

Brownstein

et al. 2022

JCM

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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.

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Section: Discussionmentioning

confidence: 99%

“…Amino acid residues conserved in all proteins are shaded in gray. The putative position of the second transmembrane (TM 2) α-helix according to [ 45 ] is indicated above the sequence. The position of the amino acid Leu117 (L117) is also given.…”

Section: Figurementioning

confidence: 99%

Molecular Features of SLC26A4 Common Variant p.L117F

Matulevičius

Bernardinelli

Brownstein

et al. 2022

JCM

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“…Eine Liste bereits untersuchter und mithilfe funktionaler Tests kategorisierter SLC26A4-Varianten wurde 2017 von Dossena et al publiziert [33].…”

Section: Molekulare Und Funktionale Untersuchungen Von Protein-variantenunclassified

Molekulare und funktionale Abklärung hereditärer Schwerhörigkeiten am Beispiel des SLC26A4-Gens

Roesch¹,

Bernardinelli

Wortmann

et al. 2020

Laryngorhinootologie

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ZusammenfassungDie in den vergangenen Jahren zunehmende Verfügbarkeit molekularer Untersuchungstechniken führt zu einer steigenden Anzahl diagnostizierter genetischer Varianten im Genom untersuchter Patienten. Am Beispiel der hereditären Innenohrschwerhörigkeit wird bei Betrachtung der Vielzahl publizierter Berichte über die mögliche Beteiligung einzelner Gene an der Pathogenese deutlich, welche Herausforderungen die Zunahme molekularer Informationen für die Interpretation mit sich bringt.In dieser Übersichtsarbeit werden anhand des Beispiels des SLC26A4-Gens und den damit verbundenen Formen einer hereditären Innenohrschwerhörigkeit die derzeit vorhandenen Möglichkeiten einer systematischen Abklärung und Interpretation dargestellt. Neben einer Beschreibung der physiologischen Funktion des resultierenden Pendrin-Proteins werden molekulare Untersuchungsmöglichkeiten zur Beurteilung der Funktion im Fall von nachgewiesenen Genvarianten erläutert. Die im Rahmen eines primär wissenschaftlichen Ansatzes resultierenden Ergebnisse auf molekularer Ebene dienen im klinischen Alltag der Interpretation hinsichtlich des kausalen Zusammenhangs zwischen einer nachgewiesenen Genvariante (Genotyp) und der Innenohrschwerhörigkeit (Phänotyp). Schließlich wird auf die mögliche Notwendigkeit einer weiteren interdisziplinären Abklärung, z. B. mithilfe einer Perchlorat-Testung der Schilddrüse, sowie therapeutische Möglichkeiten eingegangen.

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“…Conversely, specific inhibition of renal pendrin has been suggested to face hypertension and the condition of diuretic-resistant water overload [25]. Based on the crystal structure of the transmembrane domain of Deinococcus geothermalis fumarate transporter (SLC26Dg), it has been proposed that pendrin holds fourteen transmembrane alpha-helices with cytosolic N-terminal and C-terminal domains [26]. The Cterminal region contains a Sulfate Transporter and Anti-Sigma Factor Antagonist (STAS) domain and a putative consensus protein kinase A (PKA) phosphorylation motif (714)RKDT(717).…”

Section: Introductionmentioning

confidence: 99%

Functional interplay between CFTR and pendrin: physiological and pathophysiological relevance

Tamma¹,

Dossena²

2022

Front. Biosci. (Landmark Ed)

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The transport of chloride and bicarbonate across epithelia controls the pH and volume of the intracellular and luminal fluids, as well as the systemic pH and vascular volume. The anion exchanger pendrin (SLC26A4) and the cystic fibrosis transmembrane conductance regulator (CFTR) channel are expressed in the apical membrane of epithelial cells of various organs and tissues, including the airways, kidney, thyroid, and inner ear. While pendrin drives chloride reabsorption and bicarbonate, thiocyanate or iodide secretion within the apical compartment, CFTR represents a pathway for the apical efflux of chloride, bicarbonate, and possibly iodide. In the airways, pendrin and CFTR seems to be involved in alkalinization of the apical fluid via bicarbonate secretion, especially during inflammation, while CFTR also controls the volume of the apical fluid via a cAMP-dependent chloride secretion, which is stimulated by pendrin. In the kidney, pendrin is expressed in the cortical collecting duct and connecting tubule and co-localizes with CFTR in the apical membrane of β intercalated cells. Bicarbonate secretion occurs via pendrin, which also drives chloride reabsorption. A functional CFTR is required for pendrin activity. Whether CFTR stimulates pendrin via a direct molecular interaction or other mechanisms, or simply provides a pathway for chloride recycling across the apical membrane remains to be established. In the thyroid, CFTR and pendrin might have overlapping functions in driving the apical flux of iodide within the follicular lumen. In other organs, including the inner ear, the possible functional interplay between pendrin and CFTR needs to be explored.

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The Pendrin Polypeptide

Cited by 5 publications

References 114 publications

Molecular Features of SLC26A4 Common Variant p.L117F

Molecular Features of SLC26A4 Common Variant p.L117F

Molekulare und funktionale Abklärung hereditärer Schwerhörigkeiten am Beispiel des SLC26A4-Gens

Functional interplay between CFTR and pendrin: physiological and pathophysiological relevance

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