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

Silvia Dossena and Markus Paulmichl Historical Background Perspectives and Open Questions References I The Role of Pendrin in the Inner Ear Mouse Models Reveal the Role of Pendrin in the Inner Ear Introduction Synopsis of the Development of the Murine Inner Ear Pendrin Expression in the Inner Ear Mouse Models That Lack Pendrin Expression Development of the Cochlea Without Pendrin Development of the Vestibular Labyrinth Without Pendrin Mouse Models That Express Hypomorphic Pendrin Mouse Models with Spatially Limited Pendrin Expression Inner Ears Without Pendrin Expression in the Endolymphatic Sac Inner Ear Without Pendrin Expression in the Cochlea and Vestibular Labyrinth Mouse Models with Temporally Limited Pendrin Expression Pendrin Expression Is Required During a Critical Time Period During Development Pendrin Deficiency During Development Leads to Degeneration of Stria Vascularis and Causes Fluctuating and Progressive Hearing Loss Reinstatement of Pendrin Expression Alleviates Fluctuating Hearing Loss Conclusions References The Slc26a4loop Mouse Model for Pendred's Syndrome and Nonsyndromic Deafness Introduction The Slc26a4loop Mouse Is a Model for Pendred's Syndrome Slc26a4loop Is Informative for the Variable Vestibular Phenotype of Pendred's Syndrome Slc26a4loop Is Informative for the Variable Thyroid Phenotype of Pendred's Syndrome Summary References Pendrin-Linked Deafness in Humans Introduction Hearing in Humans Embryology Anatomy Physiology Impaired Hearing Hearing Loss in General Hearing Loss in Case of Pendrin Dysfunction Diagnosis Clinical Course Treatment of Hearing Loss Treatment of Hearing Loss in General Treatment of Hearing Loss in Case of Pendrin Dysfunction Conclusions References Genetic Diagnosis of Deafness Causes of Hearing Loss Environmental Causes Genetic Causes Hereditary Hearing Loss Syndromic Hearing Loss Autosomal Recessive Syndromic Hearing Loss Autosomal Dominant Syndromic Hearing Loss X-Linked Syndromic Hearing Loss Mitochondrial Syndromic Hearing Impairment Nonsyndromic Hearing Impairment Autosomal Recessive Nonsyndromic Hearing Loss Autosomal Dominant Nonsyndromic Hearing Loss X-Linked Nonsyndromic Hearing Loss Mitochondrial Nonsyndromic Hearing Loss Molecular Genetic Testing Newborn Hearing Screening Conventional and New Molecular Tools Conclusions and Perspectives References II The Role of Pendrin in the Thyroid Hypothyroidism, Subclinical Hypothyroidism and Related Diagnostic Tools The Thyroid: Anatomy, Embryology and Histology Thyroid Hormone Synthesis Thyroid Hormone Metabolism Definition of Abnormal Thyroid Function Primary and Secondary Causes of Hypothyroidism Congenital Primary Hypothyroidism Iodine Deficiency Thyroiditis Chronic Lymphocytic Thyroiditis—Hashimoto's Thyroiditis Painless Thyroiditis Postpartum Thyroiditis Subacute Granulomatous Thyroiditis—De Quervain Thyroiditis Infectious Thyroiditis Fibrous Thyroiditis—Riedel's Thyroiditis Drug-Induced Thyroid Changes Amiodarone Lithium Interferon-alpha Interleukin-2 and Other Cytokines Tyrosine Kinase Inhibitors References The Controversial Role of Pendrin in Thyroid Cell Function and in the Thyroid Phenotype in Pendred Syndrome Introduction How Does Iodide Enter the Follicular Lumen?Pendrin Anoctamin Future Directions References III The Role of Pendrin in the Kidney Pendrin and Its Partners in the Kidney: Roles in Vascular Volume and Acid Base Regulation Introduction Interaction of Pendrin with the Sodium Chloride Cotransporter NCC Pendrin and Salt Absorption Compensatory Role of Pendrin in Salt Reabsorption in the Distal Nephron in the Setting of NCC Inactivation Pendrin Expression Is Significantly Enhanced in Kidneys of NCC KO Mice Double Knockout of Pendrin and NCC Causes Severe Salt Wasting under Baseline Conditions Compensatory Role of ENaC in Salt Absorption in the Distal Nephron in the Setting of NCC Inactivation Expression of ENaC Is Enhanced in Kidneys of NCC KO Mice Effect of Amiloride on Salt Excretion in NCC KO Mice Conclusions Impact of Pendrin and NCC Downregulation on Salt, Calcium, and Water Absorption in the Collecting Duct Role of the Interplay of CaSR Signaling and Aquaporin-2 Interaction of Pendrin with CFTR and Other Chloride Transporters Pendrin and Cystic Fibrosis Conclusion Pendrin and Other Chloride Transporters Regulation of Pendrin by the Carbonic Anhydrase II and Effect of Carbonic Anhydrase Inhibitors Carbonic Anhydrase Inhibitor Acetazolamide Downregulates the Expression of Pendrin in the Kidney Synergistic Effects of Acetazolamide and Hydrochlorothiazide on Salt Excretion, Vascular Volume, and Kidney Function References IV The Role of Pendrin in the Airways The Role of Pendrin in the Airways: Links with Asthma and COPD Introduction Overview of the Signal Transduction of Interleukin-4 and Interleukin-13 and Their Significance in Bronchial Asthma Identification of Pendrin as an IL-4- or IL-13-Inducible Molecule and Its Involvement in Allergic Respiratory Inflammation Regulation of the SLC26A4 Gene by IL-4/IL-13 Pathological Roles of Pendrin/SLC26A4 in Bronchial Asthma Pathological Roles of Pendrin/SLC26A4 in Other Respiratory Conditions Pendrin in Lung: Detrimental or Beneficial?Perspectives References V The Pendrin Gene and Protein Transcriptional Regulation and Epigenetics of Pendrin Introduction The Pendrin Gene (SLC26A4/PDS) and Its Product, SLC26A4/Pendrin Protein Pendred Syndrome Expression and Function of Pendrin Pendrin in the Kidney Pendrin in the Inner Ear Pendrin in the Thyroid Gland Pendrin in the Airway Epithelium Transcriptional Regulation of Pendrin Activity Effect of Systemic pH Effect of Aldosterone Effect of Ambient Cl-Effect in Kidney Effect in Thyroid Effect of Uroguanylin Effect in Kidney Effect in Airways Effect of IL-4 and IL-13 Epigenetic Regulation of Pendrin Activity Background Epigenetics of Pendrin in Thyroid Carcinoma Epigenetics of Pendrin in Other Organs Transcriptional Regulation of Other SLC26 Genes Potential Therapeutic Implications of Pendrin Gene Modulation Conclusion References The Pendrin Polypeptide Models for Human Pendrin Structure Background Structure of STAS Domains STAS Domain-Binding Proteins SLC26Dg Crystal Structure Modeling of Human Pendrin (hPDS) Structure Proposed Substrate-Binding Site in hPDS Structure Functional and Molecular Properties of Wild-Type Pendrin and Its Variants Functional Tests for Assessing Pendrin Function Pendrin Variants with Complete or Partial Loss-of-Function, with No Change in Function, or with Gain-of-Function Subcellular Localization and Expression Levels of Pendrin Variants Potential Pendrin-Targeted Pharmacological Interventions Screening of Pendrin Ligands Rescuing Pendrin Function: Future Perspectives References

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Roles in Health and Disease
Humans In humans, many of the known moonlighting proteins function in cellular processes that can go wrong in cancer, diabetes, and other common diseases or are important in disease treatment, for example: DNA synthesis or repair; chromatin and cytoskeleton structure; angiogenesis; amino acid,...
(Moonlighting proteins : novel virulence factors in bacterial infections)
The Role of Pendrin in the Inner Ear
Mouse Models Reveal the Role of Pendrin in the Inner Ear Philine Wangemann and Andrew J. Griffith Abstract In 1896, Vaughan Pendred, MD, wrote a case report about two siblings that presented with hearing loss and goiter. This initial report was followed over the next 100 years with additional...
(The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger)
Mouse Models Reveal the Role of Pendrin in the Inner Ear
Philine Wangemann and Andrew J. Griffith Abstract In 1896, Vaughan Pendred, MD, wrote a case report about two siblings that presented with hearing loss and goiter. This initial report was followed over the next 100 years with additional cases, and the condition became known as Pendred syndrome....
(The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger)
The Role of Pendrin in the Thyroid
Hypothyroidism, Subclinical Hypothyroidism and Related Diagnostic Tools Gregor Schweighofer Zwink and Christian Pirich Abstract Thyroid hormones have a widespread effect on human metabolism. Their biochemical peculiarity is the need of iodine for their synthesis. Any lack of thyroid hormones...
(The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger)
The Controversial Role of Pendrin in Thyroid Cell Function and in the Thyroid Phenotype in Pendred Syndrome
Peter Kopp, Aigerim Bizhanova, and Liuska Pesce Abstract Thyroid hormones are essential for normal development, growth and differentiation of numerous tissues, and metabolic regulation. Structurally, they are unique because they contain iodine. Their synthesis in thyroid follicles thus requires...
(The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger)
The Role of Pendrin in the Kidney
Pendrin and Its Partners in the Kidney: Roles in Vascular Volume and Acid Base Regulation Manoocher Soleimani and Giovanna Valenti Abstract The Cl-/HCO3- exchanger pendrin (SLC26A4, PDS) is located on the apical membrane of B-intercalated cells in the kidney cortical collecting duct (CCD)...
(The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger)
Compensatory Role of Pendrin in Salt Reabsorption in the Distal Nephron in the Setting of NCC Inactivation
Based on its dual function of bicarbonate secretion and chloride reabsorption, it was originally thought that pendrin plays important roles in acid base regulation and electrolyte homeostasis under basal conditions. As noted above, the absence of any significant salt wasting in mice or human lacking...
(The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger)
The Role of Pendrin in the Airways
The Role of Pendrin in the Airways: Links with Asthma and COPD Kenji Izuhara, Shoichi Suzuki, Charity Nofziger, Masahiro Ogawa, Shoichiro Ohta, Yasuhiro Nanri, Yasutaka Mitamura, Tomohito Yoshihara, Nicoletta Pedemonte, Luis J.V. Galietta, and Markus Paulmichl Abstract Interleukin (IL)-4...
(The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger)
The Role of Pendrin in the Airways: Links with Asthma and COPD
Kenji Izuhara, Shoichi Suzuki, Charity Nofziger, Masahiro Ogawa, Shoichiro Ohta, Yasuhiro Nanri, Yasutaka Mitamura, Tomohito Yoshihara, Nicoletta Pedemonte, Luis J.V. Galietta, and Markus Paulmichl Abstract Interleukin (IL)-4 and IL-13 are related cytokines correlated with type 2 immunity involved...
(The Role of Pendrin in Health and Disease: Molecular and Functional Aspects of the SLC26A4 Anion Exchanger)
BIOCULTURAL PERSPECTIVES ON HEALTH AND DISEASE
Knowledge about the health of ancient indigenous peoples in America is limited both by geographic regions and by culturally significant periods leading up to contact. It is not surprising that no clear picture of trends in health for the many different groups has emerged. One of the best attempts to...
(Bodies and Lives in Ancient America: Health Before Columbus)