The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exc

Silvia Dossena and Markus PaulmichlHistorical BackgroundPerspectives and Open QuestionsReferencesI The Role of Pendrin in the Inner EarMouse Models Reveal the Role of Pendrin in the Inner EarIntroduction Synopsis of the Development of the Murine Inner EarPendrin Expression in the Inner EarMouse Models That Lack Pendrin ExpressionDevelopment of the Cochlea Without PendrinDevelopment of the Vestibular Labyrinth Without PendrinMouse Models That Express Hypomorphic PendrinMouse Models with Spatially Limited Pendrin ExpressionInner Ears Without Pendrin Expression in the Endolymphatic SacInner Ear Without Pendrin Expression in the Cochlea and Vestibular LabyrinthMouse Models with Temporally Limited Pendrin ExpressionPendrin Expression Is Required During a Critical Time Period During DevelopmentPendrin Deficiency During Development Leads to Degeneration of Stria Vascularis and Causes Fluctuating and Progressive Hearing LossReinstatement of Pendrin Expression Alleviates Fluctuating Hearing LossConclusionsReferencesThe Slc26a4loop Mouse Model for Pendred's Syndrome and Nonsyndromic DeafnessIntroductionThe Slc26a4loop Mouse Is a Model for Pendred's SyndromeSlc26a4loop Is Informative for the Variable Vestibular Phenotype of Pendred's SyndromeSlc26a4loop Is Informative for the Variable Thyroid Phenotype of Pendred's SyndromeSummaryReferencesPendrin-Linked Deafness in HumansIntroductionHearing in HumansEmbryologyAnatomyPhysiologyImpaired HearingHearing Loss in GeneralHearing Loss in Case of Pendrin DysfunctionDiagnosisClinical CourseTreatment of Hearing LossTreatment of Hearing Loss in GeneralTreatment of Hearing Loss in Case of Pendrin DysfunctionConclusionsReferencesGenetic Diagnosis of DeafnessCauses of Hearing LossEnvironmental CausesGenetic CausesHereditary Hearing LossSyndromic Hearing LossAutosomal Recessive Syndromic Hearing LossAutosomal Dominant Syndromic Hearing LossX-Linked Syndromic Hearing LossMitochondrial Syndromic Hearing ImpairmentNonsyndromic Hearing ImpairmentAutosomal Recessive Nonsyndromic Hearing LossAutosomal Dominant Nonsyndromic Hearing LossX-Linked Nonsyndromic Hearing LossMitochondrial Nonsyndromic Hearing LossMolecular Genetic TestingNewborn Hearing ScreeningConventional and New Molecular ToolsConclusions and PerspectivesReferencesII The Role of Pendrin in the ThyroidHypothyroidism, Subclinical Hypothyroidism and Related Diagnostic ToolsThe Thyroid: Anatomy, Embryology and HistologyThyroid Hormone SynthesisThyroid Hormone MetabolismDefinition of Abnormal Thyroid FunctionPrimary and Secondary Causes of HypothyroidismCongenital Primary HypothyroidismIodine DeficiencyThyroiditisChronic Lymphocytic Thyroiditis—Hashimoto's ThyroiditisPainless ThyroiditisPostpartum ThyroiditisSubacute Granulomatous Thyroiditis—De Quervain ThyroiditisInfectious ThyroiditisFibrous Thyroiditis—Riedel's ThyroiditisDrug-Induced Thyroid ChangesAmiodaroneLithiumInterferon-alphaInterleukin-2 and Other CytokinesTyrosine Kinase InhibitorsReferencesThe Controversial Role of Pendrin in Thyroid Cell Function and in the Thyroid Phenotype in Pendred SyndromeIntroductionHow Does Iodide Enter the Follicular Lumen?PendrinAnoctaminFuture DirectionsReferencesIII The Role of Pendrin in the KidneyPendrin and Its Partners in the Kidney: Roles in Vascular Volume and Acid Base RegulationIntroductionInteraction of Pendrin with the Sodium Chloride Cotransporter NCCPendrin and Salt AbsorptionCompensatory Role of Pendrin in Salt Reabsorption in the Distal Nephron in the Setting of NCC InactivationPendrin Expression Is Significantly Enhanced in Kidneys of NCC KO MiceDouble Knockout of Pendrin and NCC Causes Severe Salt Wasting under Baseline ConditionsCompensatory Role of ENaC in Salt Absorption in the Distal Nephron in the Setting of NCC InactivationExpression of ENaC Is Enhanced in Kidneys of NCC KO MiceEffect of Amiloride on Salt Excretion in NCC KO MiceConclusionsImpact of Pendrin and NCC Downregulation on Salt, Calcium, and Water Absorption in the Collecting DuctRole of the Interplay of CaSR Signaling and Aquaporin-2Interaction of Pendrin with CFTR and Other Chloride TransportersPendrin and Cystic FibrosisConclusionPendrin and Other Chloride TransportersRegulation of Pendrin by the Carbonic Anhydrase II and Effect of Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitor Acetazolamide Downregulates the Expression of Pendrin in the KidneySynergistic Effects of Acetazolamide and Hydrochlorothiazide on Salt Excretion, Vascular Volume, and Kidney FunctionReferencesIV The Role of Pendrin in the AirwaysThe Role of Pendrin in the Airways: Links with Asthma and COPDIntroductionOverview of the Signal Transduction of Interleukin-4 and Interleukin-13 and Their Significance in Bronchial AsthmaIdentification of Pendrin as an IL-4- or IL-13-Inducible Molecule and Its Involvement in Allergic Respiratory InflammationRegulation of the SLC26A4 Gene by IL-4/IL-13Pathological Roles of Pendrin/SLC26A4 in Bronchial AsthmaPathological Roles of Pendrin/SLC26A4 in Other Respiratory ConditionsPendrin in Lung: Detrimental or Beneficial?PerspectivesReferencesV The Pendrin Gene and ProteinTranscriptional Regulation and Epigenetics of PendrinIntroductionThe Pendrin Gene (SLC26A4/PDS) and Its Product, SLC26A4/Pendrin ProteinPendred SyndromeExpression and Function of PendrinPendrin in the KidneyPendrin in the Inner EarPendrin in the Thyroid GlandPendrin in the Airway EpitheliumTranscriptional Regulation of Pendrin ActivityEffect of Systemic pHEffect of AldosteroneEffect of Ambient Cl-Effect in KidneyEffect in ThyroidEffect of UroguanylinEffect in KidneyEffect in AirwaysEffect of IL-4 and IL-13Epigenetic Regulation of Pendrin ActivityBackgroundEpigenetics of Pendrin in Thyroid CarcinomaEpigenetics of Pendrin in Other OrgansTranscriptional Regulation of Other SLC26 GenesPotential Therapeutic Implications of Pendrin Gene ModulationConclusionReferencesThe Pendrin PolypeptideModels for Human Pendrin StructureBackgroundStructure of STAS DomainsSTAS Domain-Binding ProteinsSLC26Dg Crystal StructureModeling of Human Pendrin (hPDS) StructureProposed Substrate-Binding Site in hPDS StructureFunctional and Molecular Properties of Wild-Type Pendrin and Its VariantsFunctional Tests for Assessing Pendrin FunctionPendrin Variants with Complete or Partial Loss-of-Function, with No Change in Function, or with Gain-of-FunctionSubcellular Localization and Expression Levels of Pendrin VariantsPotential Pendrin-Targeted Pharmacological InterventionsScreening of Pendrin LigandsRescuing Pendrin Function: Future PerspectivesReferences
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