Table Of ContentSilvia Dossena · Markus Paulmichl
Editors
The Role of
Pendrin in
Health and
Disease
Molecular and Functional Aspects of the
SLC26A4 Anion Exchanger
The Role of Pendrin in Health and Disease
Silvia Dossena • Markus Paulmichl
Editors
The Role of Pendrin
in Health and Disease
Molecular and Functional Aspects
of the SLC26A4 Anion Exchanger
Editors
Silvia Dossena Markus Paulmichl
Paracelsus Medical University Paracelsus Medical University
Institute of Pharmacology Institute of Pharmacology
and Toxicology and Toxicology
Salzburg Salzburg
Austria Austria
ISBN 978-3-319-43285-4 ISBN 978-3-319-43287-8 (eBook)
DOI 10.1007/978-3-319-43287-8
Library of Congress Control Number: 2017931637
© Springer International Publishing Switzerland 2017
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To Florian Lang, for the continuous support
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source of inspiration
Preface
Disease is the consequence of deranged molecular events affecting the function of
cells, tissues, organs and eventually the whole body of living organisms. Therefore,
understanding a pathophysiological process often requires a multidisciplinary
approach and the joint efforts of scientists from the biochemical, biological,
biomedical and clinical fields.
The Role of Pendrin in Health and Disease has the peculiarity of focusing on an
individual molecule, of which a detailed description of the multifaceted function is
provided from different points of view. Pendrin is a protein localized in the plasma
membrane of cells in various tissues and organs and transports negatively charged
ions. Malfunction of pendrin causes genetically inherited diseases of which hearing
loss is the main feature, such as Pendred syndrome and non-syndromic deafness.
The main aim of this book is to summarize and contribute to the diffusion of
the current knowledge on the genetics, molecular biology and physiology of pen-
drin as well as the derangements occurring as a consequence of alterations in its
function. After an introductory historical background (Chap. 1), the book is orga-
nized into five parts, of which the first four illustrate the pathophysiology of pen-
drin in the inner ear, thyroid, kidney and airways, respectively. Specifically,
Chaps. 2 and 3 describe mouse models that greatly contributed to the understand-
ing of pendrin function and dysfunction. Chapters 4, 5 and 6 focus on clinical
aspects of the inner ear and thyroid alterations in case of pendrin malfunction, and
Chaps. 7, 8 and 9 illustrate how combined in vitro and in vivo studies integrate in
the understanding of the molecular pathophysiology of pendrin. Part V includes
two chapters focusing on the genetic, epigenetic, structural and molecular aspects
of pendrin.
Although mainly focused on pendrin, some chapters of this book may be of great
interest for scientists not directly involved in pendrin research. Specifically, Chap. 4
includes the anatomy of the inner ear, Chap. 5 is a precious guide for geneticists in
the challenging effort of providing a genetic diagnosis of deafness and Chap. 6
illustrates aspects of thyroid pathology. This book, besides providing scientists with
a detailed picture of the current knowledge on pendrin, may help otolaryngologists
and endocrinologists in the diagnosis of Pendred syndrome and pendrin-related
deafness and can be a useful tool for PhD and undergraduate students undertaking
studies in physiology and pathology.
vii
viii Preface
We have appreciated the contribution of scientists actively engaged since years
in the research on various aspects of pendrin genetics, pathophysiology and phar-
macology; to ensure a fresh perspective, some of the chapters are co-authored by
young investigators.
We gratefully acknowledge all authors that, after working at the laboratory
bench, patient’s bedside or in the classroom, were able to find the time to contribute
to The Role of Pendrin in Health and Disease.
Also, as science is an ever-evolving discipline and new knowledge is gathered
quickly and continuously, we apologize for possible omission of information made
accessible during the last steps of the editorial process of this book.
Salzburg, Austria Silvia Dossena
Salzburg, Austria Markus Paulmichl
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Silvia Dossena and Markus Paulmichl
Part I The Role of Pendrin in the Inner Ear
2 Mouse Models Reveal the Role of Pendrin in the Inner Ear . . . . . . . . . 7
Philine Wangemann and Andrew J. Griffith
3 The Slc26a4loop Mouse Model for Pendred’s Syndrome
and Nonsyndromic Deafness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Amiel A. Dror and Karen B. Avraham
4 Pendrin-Linked Deafness in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Sebastian Roesch, Miklós Tóth, and Gerd Rasp
5 Genetic Diagnosis of Deafness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Sueli Matilde da Silva Costa, Priscila Zonzini Ramos,
Fábio Tadeu Arrojo Martins, and Edi Lúcia Sartorato
Part II The Role of Pendrin in the Thyroid
6 Hypothyroidism, Subclinical Hypothyroidism and Related
Diagnostic Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Gregor Schweighofer Zwink and Christian Pirich
7 The Controversial Role of Pendrin in Thyroid Cell Function
and in the Thyroid Phenotype in Pendred Syndrome . . . . . . . . . . . . . 107
Peter Kopp, Aigerim Bizhanova, and Liuska Pesce
Part III The Role of Pendrin in the Kidney
8 Pendrin and Its Partners in the Kidney: Roles in Vascular
Volume and Acid Base Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Manoocher Soleimani and Giovanna Valenti
ix
x Contents
Part IV The Role of Pendrin in the Airways
9 The Role of Pendrin in the Airways: Links with Asthma and COPD 141
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
Part V The Pendrin Gene and Protein
10 Transcriptional Regulation and Epigenetics of Pendrin . . . . . . . . . . . 157
Julia Rozenfeld, Charity Nofziger, Orly Kladnitsky, Seth L. Alper,
and Israel Zelikovic
11 The Pendrin Polypeptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Silvia Dossena, Emanuele Bernardinelli, Alok K. Sharma,
Seth L. Alper, and Markus Paulmichl
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Introduction 1
Silvia Dossena and Markus Paulmichl
1.1 Historical Background
Sometimes in science, it is important to address the right question. It was in 1896
that a young doctor, Vaughan Pendred (1869–1946), observed two cases of deaf-
mutism and goiter in a large Irish family resident in Durham (Pearce 2007) and
asked himself, as well as the readers of the prestigious medical journal The Lancet:
“Why this association?” (Box 1.1) (Pendred 1896). In 1960, Fraser, Morgans, and
Trotter proposed the eponymous of “Pendred syndrome” for defining the associa-
tion of congenital deafness and sporadic goiter. The same authors attempted to
explain the reason of this association with an interference between thyroxine syn-
thesis and auditory function by toxic substances produced by an aberrant metabolic
pathway (Fraser et al. 1960; Fraser 1965), a hypothesis that was never demonstrated.
In the same period, Thould and Scowen postulated that deafness in Pendred syn-
drome could arise from an inadequate exposure to thyroid hormones in utero
(Thould and Scowen 1964). This hypothesis was refuted by the fact that the nature
of deafness caused by hypothyroidism – nerve (De Vos 1963) or conduction type –
is different from that observed in Pendred syndrome (perceptive, i.e., sensorineural)
(Woolf 1965), and the cause of the syndrome remained obscure.
Several years later, the advent of molecular genetics greatly accelerated the dis-
covery of genes involved in disease. In 1996, Coyle and Sheffield independently
showed that Pendred syndrome maps to chromosome 7q, in the region containing
the gene of nonsyndromic deafness DFNB4 (Coyle et al. 1996; Sheffield et al.
1996). In 1997, Everett and collaborators, using a positional cloning strategy, identi-
fied the gene mutated in Pendred syndrome (formerly called PDS) and described
three potentially deleterious sequence alterations segregating with the disease
S. Dossena (*) • M. Paulmichl
Institute of Pharmacology and Toxicology, Paracelsus Medical University,
Strubergasse 21, Salzburg A-5020, Austria
e-mail: [email protected]; [email protected]
© Springer International Publishing Switzerland 2017 1
S. Dossena, M. Paulmichl (eds.), The Role of Pendrin in Health and Disease,
DOI 10.1007/978-3-319-43287-8_1
