G Proteins, Receptors, and Disease

323 Pages·1998·10.461 MB·English

by  Allen M. Spiegel MD (auth.), Allen M. Spiegel MD (eds.)

G
PROTEINS,
RECEPTORS,
AND
DISFASE
CONTEMPORARY ENDOCRINOLOGY
P. Michael Conn,
SERIES EDITOR
6. G Proteins, Receptors, and Disease, edited by ALLEN M SPIEGEL, 1998
5. Natriuretic Peptides in Health and Disease, edited by WILLIS K. SAMSON
AND ELLIS R. LEVIN, 1997
4. Endocrinology of Critical Diseases, edited by K. PATRICK DBER, 1997
3. Diseases oft he Pituitary: Diagnosis and Treatment, edited by
MARGARET E. WIERMAN, 1997
2. Diseases oft he Thyroid, edited by LEWIS E. BRAVERMAN, 1997
1. Endocrinology oft he Vasculature, edited by JAMES R. SOWERS, 1996
G
PROTEINS, RECEPTORS,
AND DISEASE
Edited by
M.
ALLEN SPIEGEL, MD
Chief, Metabolic Diseases Branch,
National Institute ofD iabetes
and Digestive and Kidney Diseases,
National Institutes ofH ealth, Bethesda, MD
Springer Science+Business Media, LLC
© 1998 Springer Seienee+Business Media New York
Origina1ly published by Humana Press Ine. 1998
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10 9 8 7 6 5 4 3 2 I
G proteins, receptors, and disease/edited by Allen M. Spiegel
p. cm.--(Contemporary endocrinologyTM; 6)
Includes index.
ISBN 978-1-4612-7290-8 ISBN 978-1-4612-1802-9 (eBook)
DOI 10.1007/978-1-4612-1802-9
1. G proteins-Physiological effect. 2. G proteins-Pathophysiology 3. Endocrine glands-Oiseases.
4. Cellular signal transduction 5. Pathology, Molecular. 1. Spiegel, Allen M. II. Series: Contemporary
endocrinology (Totowa, NJ);
[ONLM: 1. G proteins-physiology. 2. Receptors. Cell Surface-physiology. 3. Endocrine Oiseases
genetics. 4. Signal Transduction. QU 55 G II \3 1998]
QP552.G 16G24 1998
616,4' 07 l--dc2 I
DNLMIDLC
for Library of Congress 97-51985
CIP
PREFACE
"Theoretically, one should obtain essentially the same clinical picture from failure of
an end-organ to respond to a hormone as from a decreased production or absence of said
hormone." With these words, Fuller Albright began his now classic paper describing a
novel disease, pseudo hypoparathyroidism (PHP), and a novel concept, hormone resis
tance as a cause ofd isease. Soon, other hormone resistance disorders such as nephrogenic
diabetes insipidus (NDI) were recognized, and the concept was extended to resistance to
other substances such as calcium ions in familial hypocalciuric hypercalcemia (FHH).
Later, diseases characterized by excess rather than deficient hormone action such as
McCune-Albright syndrome (MAS) and familial male precocious puberty (FMPP) were
recognized to be caused by autonomous endocrine hyperfunction. Although many
i!!vestigators provided careful and detailed descriptions of the clinical features of
these and other related endocrine disorders, an understanding of pathogenesis proved
elusive for many years.
In just the past few years, we have gone from clinical description to a molecular
understanding oft hese interesting disorders. This remarkable progress reflects a synthe
sis of three distinct, but now overlapping, areas of biomedical research: the aforemen
tioned recognition and careful clinical description of specific diseases, the elucidation
of the basic mechanisms of signal transduction, and the application of the powerful tools
of molecular biology and genetics. Fundamental studies on the mechanisms of hormone
action by Rodbell and colleagues at NIH culminated in the discovery of a major signal
transduction pathway involving heterotrimeric G proteins. Hundreds of G-protein
coupled receptors (GPCR), over a dozen G proteins, and a comparable number of effec
tors regulated by G proteins have now been identified and characterized at the molecular
and cellular level. Identification and molecular characterization of these signaling pro
teins and the genes that encode them allowed them to be tested as candidates responsible
for diseases of hormone resistance or endocrine hyperfunction. Powerful tools of
molecular biology and genetics such as the polymerase chain reaction and gene mapping
facilitated testing such hypotheses.
The present volume offers the reader the fruits of the application of molecular
biology and genetics to studies of G-protein-coupled signal transduction and dis
ease. Two important and related themes run through each chapter of the book:
Many diseases of hormone resistance and of endocrine hyperfunction are caused by
loss- and gain-of-function mutations in G proteins or GPCR and the studies of such
diseases and the mutations that cause them offer unique insights into the physiologic
relevance, structure and function of the involved G protein or GPCR. Many of the
chapters include, in addition to discussion of naturally occurring human (or in some
instances other mammalian) disorders, a discussion ofa rtificially created disorders using
transgenic and gene knockout approaches in mice. The latter also offers powerful
insights into G protein and GPCR structure and function, and also suggests new candi
date genes for human disorders whose pathogenesis remains unclear.
v
VI Preface
An introductory chapter provides an overview ofG-protein-coupled signal transduc
tion and its relevance to human disease, not only to endocrine disorders, which are the
main focus of the book and are covered in detail in the ensuing chapters, but also to
other disorders in which G-protein and GPCR mutations playa role, such as retinitis
pigmentosa, congenital megacolon, and AIDS. The next section of the book (Chap
ters 2-6) addresses G proteins, disorders such as PHP and MAS caused by G-protein
mutations, and insights gained from G protein mouse gene knockouts. The remain
der of the book contains chapters on various GPCR. Chapters 7-9 consider glyco
protein hormone receptors and diseases such as FMPP and hyperthyroidism caused
by mutations in these receptors. Chapters 10-15 cover receptors for other peptide
hormones such as vasopressin, PTH, ACTH, MSH, as well as the calcium ion
receptor. Diseases owing to mutations in these receptors include NDI, FHH, and
familial glucocorticoid deficiency. The final section of the book (Chapters 16-18)
deals with ~-adrenergic and dopamine receptors, including studies on transgenic and
knockout mice. Although no single mutation in one of these receptors has clearly
been identified as the cause of a human disease, identification of an association
between a ~3-adrenergic receptor polymorphism and obesity (Chapter 18) high
lights the possible contribution of subtle differences in G-protein and GPCR struc
ture to polygenic disorders such as type II diabetes and hypertension.
I hope the reader will share the sense of excitement as leading investigators depict
in their respective chapters the discovery of causes for diseases that were mysterious
for many years. The impact of these discoveries for disease diagnosis and our appre
ciation of the structure and function of the involved G proteins and GPCR has been
immediate. As has been the case in other parts of the human genetics revolution, the
impact on disease prevention and treatment has been less dramatic. A thorough
understanding of molecular pathogenesis, nonetheless, should provide the foundation
for future efforts directed at prevention and cure of these diseases. With eventual
progress in gene therapy and other approaches both old and new, I expect that future
versions of these chapters will include expanded sections on the prevention and
treatment of their respective diseases.
Allen M. Spiegel, MD
CONTENTS
Preface ........................................................................................................ v
Contributors .............................................................................................. ix
1 Introduction to G-Protein-Coupled Signal Transduction
and Human Disease ...................................................................... 1
Allen M. Spiegel
2 Albright Hereditary Osteodystrophy, Pseudohypopara-
thyroidism, and Gs Deficiency ................................................... 23
Lee S. Weinstein
3 Gas-Activating Mutations: A Cause ofA cromegaly,
Thyroid Adenomas, Fibrous Dysplasia, and the McCune-
Albright Syndrome ...................................................................... 57
Allen M. Spiegel
4 Ulcerative Colitis in Mice Lacking Gai2 ................................................. 71
Uwe Rudolph and Lutz Birnbaumer
5 G Proteins Regulating Insulin Action and Obesity:
Analysis by Conditional, Targeted Expression
ofA ntisense RNA in vivo ............................................................ 85
Craig C. Malbon, Patricia Galvin-Parton,
Hsien-yu Wang, Jun Hua Guo, and Christopher M. Moxham
6 Ga12- and Ga13-Subunits of Heterotrimeric G Proteins:
A Novel Family of Oncogenes .................................................. 101
J Silvio Gutkind, Omar A. Coso, and Ningzhi Xu
7 Hypo- and Hyperthyroidism Caused by Mutations
of the TSH Receptor ................................................................. 119
Gilbert Vassart
8 Disorders Caused by Mutations of the Lutropinl
Choriogonadotropin Receptor Gene ........................................ 139
Andrew Shenker
9 Inactivating and Activating Mutations of the FSH
Receptor Gene .......................................................................... 153
I/po T. Huhtaniemi
10 Nephrogenic Diabetes Insipidus and Vasopressin
Receptor Mutations .................................................................. 167
Daniel G. Bichet
11 Disorders with Increased or Decreased Responsiveness
to Extracellular Ca2+ Owing to Mutations in the
Ca2+o -Sensing Receptor ........................................................... 181
Edward M. Brown, Martin Pollak, Mei Bai,
and Steven C. Hebert
vii
viii Contents
12 Constitutively Active PTH/PTHrP Receptors Cause
Jansen's Metaphyseal Chondrodysplasia ................................. 205
Harald Juppner
13 Mutation of the Growth Hormone-Releasing
Hormone Receptor in the little Mouse ..................................... 217
Kelly E. Mayo, Venita /. DeAlmeida, Kenneth C. Wu,
and Paul A. Godfrey
14 Functional Variants of the MSH Receptor (MCI-R), Agouti,
and Their Effects on Mammalian Pigmentation ...................... 231
Dongsi Lu, Carrie Haskell-Luevano, Dag Inge Vage,
and Roger D. Cone
15 ACTH Resistance Syndromes ...................................................... 261
Constantine Tsigos and George P. Chrousos
16 Altering Adrenergic Signaling and Cardiac Function
in Transgenic Mice ................................................................... 271
Walter 1. Koch and Robert 1. Lefkowitz
17 Dopamine Receptors in Human Disease:
Lessons from Targeted Mouse Mutants ................................... 285
Domenico Accili, John Drago, and Sara Fuchs
18 The ~3-Adrenergic Receptor and Susceptibility to Obesity,
the Insulin Resistance Syndrome, and Noninsulin-
Dependent Diabetes Mellitus ................................................... 301
Jeremy Walston, Kristi Silver, and Alan R. Shuldiner
Index ....................................................................................................... 321
CONTRIBUTORS
DOMENICO ACCILI, MD, Developmental Endocrinology Branch, National Institute
of Child Health and Human Development, Bethesda, MD
MEl BAI, PHD, Endocrine-Hypertension and Renal Divisions, Department ofM edicine,
Brigham and Women's Hospital, Boston, MA
DANIEL G. BICHET, MD, Service de Nephrologie et Centre de Recherche, Hopital
du Sacre-Coeur de Montreal, Quebec, Canada
LUTZ BIRNBAUMER, PHD, Department ofA nesthesiology, University of California
School ofM edicine, Los Angeles, CA
EDWARD M. BROWN, MD, Endocrine-Hypertension Division, Brigham and Women's
Hospital, Boston, MA
GEORGE P. CHROUSOS, MD, Developmental Endocrinology Branch, National Institute
of Child Health and Human Development, National Institutes ofH ealth,
Bethesda, MD
ROGER D. CONE, PHD, The Vollum Institutefor Advanced Biomedical Research,
Oregon Health Sciences University, Portland, OR
OMAR A. Coso, PHD, Molecular Signaling Unit, Laboratory of Cellular Development
and Oncology, National Institute ofD ental Research, National Institutes ofH ealth,
Bethesda, MD
VENITA I. DEALMEIDA, MS, Department ofB iochemistry, Molecular Biology, and Cell
Biology, Northwestern UniverSity, Evanston, IL
JOHN DRAGO, MD, PHD, Neuroscience Laboratory, Department ofA natomy, Monash
University, Clayton, Victoria, Australia
SARA FUCHS, PHD, Department ofI mmunology, The Weizmann Institute ofS cience,
Rehovot, Israel
PATRICIA GALVIN-PARTON, MD, University Medical Center, State University ofN ew
York, Stony Brook, NY
PAUL A. GODFREY, BS, Department ofB iochemistry, Molecular Biology, and Cell
Biology, Northwestern University, Evanston, IL
JUN HUA Guo, MD, Departments ofM olecular Pharmacology
and Pediatrics,University Medical Center, State University ofN ew York,
Stony Brook, NY
1. SILVIO GUTKIND, PHD, National Institute ofD ental Research, National Institutes
ofH ealth, Bethesda, MD
CARRIE HASKELL-LUEVANO, PHD,The Vollum Institutefor Advanced
Biomedical Research, Oregon Health Sciences University,
Portland, OR
STEVEN C. HEBERT, MD, Endocrine-Hypertension and Renal Divisions, Department
ofM edicine, Brigham and Women's Hospital, Boston, MA
ILPO T. HUHTANIEMI, MD, PHD, Department ofP hysiology, University ofTurku, Finland
HARALD JUPPNER, MD, Endocrine Unit, Department ofM edicine and Children's
Service, Massachusetts General Hospital and Harvard Medical School,
Boston, MA
ix
x Contributors
WALTER J. KOCH, PHD, Department ofS urgery, Howard Hughes Medical Institute,
Duke University Medical Center, Durham, NC
ROBERT J. LEFKOWITZ, MD, Department ofM edicine and Biochemistry, Howard
Hughes Medical Institute, Duke University Medical Center, Durham NC
DONGS I Lu, PHD, The Vollum Institutefor Advanced Biomedical Research, Oregon
Health Sciences University, Portland, OR
CRAIG C. MALBON, PHD, Departments ofM olecular Pharmacology and Pediatrics,
University Medical Center, State University ofN ew York,
Stony Brook, NY
KELLY E. MAYO, PHD, Department ofB iochemistry, Molecular Biology, and Cell
Biology, Northwestern University, Evanston, IL
CHRISTOPHER M. MOXHAM, PHD, Department ofM olecular Pharmacology and Pediat
rics, University Medical Center, State University ofN ew York, Stony Brook, NY
MARTIN POLLAK, MD, Endocrine-Hypertension and Renal Divisions,
Department ofM edicine, Brigham and Women's Hospital, Boston, MA
U WE RUDOLPH, MD, Institute ofP harmacology, University ofZ urich,
Zurich, Switzerland
ANDREW SHENKER, MD, PHD, Division ofE ndocrinology, Department ofP ediatrics,
Children's Memorial Hospital and Northwestern University Medical School,
Chicago,IL
ALAN R. SHULDINER, MD, Division ofD iabetes, Obesity, and Nutrition,
University ofM aryland, Baltimore, MD
KRISTI SILVER, MD, Division ofE ndocrinology, fohns Hopkins University School
ofM edicine, Baltimore, MD
ALLEN M. SPIEGEL, MD, Metabolic Diseases Branch, National Institute of Diabetes
and Digestive and Kidney Diseases, National Institutes ofH ealth, Bethesda, MD
CONSTANTINE TSIGOS, MD, PHD, Department ofE xperimental Physiology, University
ofA thens Medical School, Greece
DAG INGE V AGE, PHD, Department ofA nimal Science, Agricultural University
ofN orway, As, Norway
GILBERT V ASSART, MD, PHD, Department ofM edical Genetics, Institute
ofI nterdisciplinary Research, Universite Libre de Bruxelles, Belgium
JEREMY WALSTON, MD, Division of Geriatric Medicine and Gerontology, fohns
Hopkins University School ofM edicine, Baltimore, MD
HSIEN~YU WANG, PHD, Department ofP hysiology and Biophysics, University Medical
Center, State University ofN ew York, Stony Brook, NY
LEE S. WEINSTEIN, MD, Metabolic Diseases Branch, National Institute ofD iabetes,
Digestive, and Kidney Diseases, National Institutes ofH ealth, Bethesda, MD
KENNETH C. Wu, BS, Department ofB iochemistry, Molecular Biology, and Cell
Biology, Northwestern University, Evanston, IL
NINGZHI Xu, MD, Molecular Signaling Unit, Laboratory of Cellular Development
and Oncology, National Institute ofD ental Research, National Institutes
ofH ealth, Bethesda, MD