Principles of Molecular Medicine

1070 Pages·1998·256.091 MB·English

by  Sarah H. Elsea, Pragna I. Patel (auth.), J. Larry Jameson MD, PhD (eds.)

PRINCIPLES OF MOLECULAR MEDICINE
SECTION EDITORS
DENNIS AUSIELLO, MD MICHAEL J. MCPHAUL, MD
DEPARTMENT OF MEDICINE DEPARTMENT OF INTERNAL MEDICINE
MASSACHUSETTS GENERAL HOSPITAL UNIVERSITY OF TEXAS
BOSTON, MA SOUTHWESTERN MEDICAL CENTER
DALLAS, TX
ANDREA BALLABIO, MD
CHARLES 8. NEMEROFF, MD, PhD
TELETHON INSTITUTE OF GENETICS
AND MEDICINE DEPARTMENT OF PSYCHIATRY
(TIGEM) AND BEHAVIORAL MEDICINE
MILANO, ITALY EMORY UNIVERSITY SCHOOL OF MEDICINE
ATLANTA, GA
MICHAEL J. HOLTZMAN, MD
jAMES C. REYNOLDS, MD
DIVISION OF PULMONARY
AND CRITICAL CARE MEDICINE DIVISION OF GASTROENTEROLOGY
ST. LOUIS, MO AND HEPA TOLOGY
ALLEGHENY UNIVERSITY
ETHYLIN WANG jABS, MD OF THE HEALTH SCIENCES
PHILADELPHIA, PA
CENTER FOR MEDICAL GENETICS
jOHNS HOPKINS UNIVERSITY SCHOOL
ANTHONY ROSENZWEIG, MD
OF MEDICINE
BALTIMORE, MD CARDIAC UNIT AND CARDIOVASCULAR
RESEARCH INSTITUTE
LAURENCE KEDES, MD MASSACHUSETTS GENERAL HOSPITAL
BOSTON, MA
INSTITUTE FOR GENETIC MEDICINE
AND PROGRAM FOR GENE THERAPY
SWEE LAY THEIN, MRCP, FRCPath
UNIVERSITY OF SOUTHERN CALIFORNIA
SCHOOL OF MEDICINE MRC MOLECULAR HAEMOTOLOGY UNIT
LOS ANGELES, CA INSTITUTE OF MOLECULAR MEDICINE
jOHN RADCLIFF HOSPITAL, HEADINGTON
THOMAS S. KUPPER, MD OXFORD, UK
DERMATOLOGY DIVISION
RALPH C. WILLIAMS, JR., MD
BRIGHAM AND WOMEN'S HOSPITAL
BOSTON, MA DIVISION OF RHEUMATOLOGY
DEPARTMENT OF MEDICINE
jOSEPH 8. MARTIN, MD, PhD UNIVERSITY OF FLORIDA
GAINESVILLE, FL
FACULTY OF MEDICINE
HARVARD MEDICAL SCHOOL
BOSTON, MA
PRINCIPLES OF
MOLECULAR
MEDICINE
EDITED BY
J.
LARRY jAMESON, MD, PhD
NORTHWESTERN UNIVERSITY MEDICAL SCHOOL
IL
CHICAGO,
FOREWORD BY
FRANCIS S. COLLINS, MD, PhD
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
BETHESDA, MD
*
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
© 1998 Springer Science+ Business Media New York
Originally published by Humana Press Inc. in 1998
Softcover reprint of the hardcover I st edition 1998
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Library of Congress Cataloging-in-Publication Data
Principles of molecular medicine I edited by J. Larry Jameson
foreword by Francis S. Collins.
p. em.
Includes index.
ISBN 978-1-4757-6272-3 ISBN 978-1-59259-726-0 (eBook)
DOI 10.1007/978-1-59259-726-0
I. Medical genetics. 2. Pathology, Molecular. 3. Molecular biology.
I. Jameson, J. Larry.
[DNLM: I. Genetics, Medical. 2. Molecular Biology. QZ 50 P9573
1998]
RB155.P695 1998
616'.042-dc21
DNLM/DLC
for Library of Congress 98-17729
CIP
Foreword
Until recently, medical genetics and molecular medicine the initiation in 1998 of an aggressive new genome project
were considered the exclusive province of academic spe goal, cataloging all common human sequence variations, it
cialists in tertiary-care medical centers. Queried about their is expected that the weaker polygenic contributors to virtu
familiarity with molecular genetic aspects of clinical medi ally all diseases will begin to be discerned. Many conse
cine, most primary-care providers only a few years ago quences will result. Individualized preventive medicine
would have responded that such matters were irrelevant to strategies, rooted in the gene-based determination of future
their daily practice. risk of illness, will become part of the regular practice of
Yet few could say that today. Few internists or general medicine. New designer drugs, based not on empiricism but
practitioners have not prescribed recombinant insulin, tPA, on a detailed understanding ofthe molecular pathogenesis of
or erythropoetin; few pediatricians have not gone through disease, will appear. Pharmacogenomics, wherein the effi
the molecular evaluation of a child with dysmorphology or cacy and toxicity of a particular drug regimen can be pre
learning disability; few obstetricians have not performed dicted based on patient genotype, will become a standard
amniocentesis or CVS for couples at increased genetic risk; component ofd esigning optimum therapy for the individual.
and few general surgeons have not faced penetrating ques And gene therapy, fed by a wealth of disease-gene discov
tions about the role ofg enetic testing or prophylactic surgery eries, will mature into a significant part of the physician's
from women with a strong family history ofbreast or ovarian armamentarium against disease.
cancer. As we watch this train coming down the track, this is an
This level of emergence of molecular genetics into clini ideal time to collect information about molecular medicine
cal medicine is still quite modest, however, compared to into one authoritative text. Principles ofM olecular Medicine
what is coming. As the human genome project hurtles aims to do just that, bridging the current gap between basic
toward completion of the sequence of a reference human science and the bedside. It will thus be useful to
genome, and the identification of all human genes, by 2005, researchers and clinicians alike. With more than 100 chapters
the pace of revelations about human illness will continue to covering a wide variety of topics, its distinguished
accelerate. Until recently, most disease-gene discoveries cohort of section editors, and its abundant tables and illustra
have related to single-gene disorders (cystic fibrosis, fragile tions, it provides an accessible and much needed manual to the
X syndrome, and so on) or to Mendelian subsets of more present and the future of molecular genetics and medicine.
common illnesses (BRCAl and BRCA2, the hereditary
nonpolyposis colon cancer syndromes, and so on). But with Francis S. Collins
v
Preface
For most physicians, molecular medicine and genetics with many lucid figures that depict cellular and genetic pathways.
have not traditionally played a major role in day-to-day clini And we have placed particular emphasis on themolecularmecha
cal practice. However, new insights into the molecular basis nisms of disease and on those new concepts resulting from
of disease are being generated at an ever-increasing rate, application of the tools of molecular biology. An especially
resulting in a transformation in our understanding and man exciting dimension of the book is the translation of the many
agement ofd iseases. This explosion of information has been recent advances in research into clinically useful information;
ignited by a variety of technological advances, and has been each of our authors has attempted to project the future implica
fueled by the rapid progress of the human genome project. tions of recent developments in their specialty areas.
It is widely recognized that molecular biology is now caus Beyond the insights afforded into the pathophysiology of
ing a paradigm shift in the teaching and practice ofm edicine. disease, it can be argued that genetics plays a role in virtually
The promise of molecular medicine is exciting, but there are every medical condition. It has been estimated that the human
also great challenges in the integration of this rapidly ad genome contains between 50,000 and 80,000 genes. Though
vancing field into our understanding and treatment of dis many diseases are caused by mutations in critical genes, it is
ease. Principles ofM olecular Medicine attempts to close the becoming increasingly evident that one's "genetic back
gap between traditional textbooks of medicine and the bur ground" can result in predisposition to many diseases or can
geoning database of new knowledge that has been generated modify the host response to environmental events. In some
by molecular biology. cases, such as hypertension and cardiovascular disease, the
The book's title, Principles of Molecular Medicine, genetic contributions are polygenic, and we are still in
reflects our effort to translate the advances provided by the early stages of identifying the many genes ihat contribute
genetics and molecular biology into each of the major spe to these conditions. In other instances, such as hemophilia,
cialties of medicine. By analogy with traditional textbooks cystic fibrosis, and hundreds of other disorders, the respon
of medicine, the book is organized according to major organ sible genes have already been well-characterized.
systems. This format is familiar to most medical readers and From one perspective, the onslaught of new information
thus conforms to the specialty areas of many authors and can seem daunting and difficult to assimilate, particularly
readers. We believe that this book will be of value to a broad because much ofthe technology and terminology is new. Ironi
audience that includes sophisticated students, specialists cally, the new insights provided can in fact greatly simplify
who are seeking updates in their own areas or on topics that areas that were previously mysterious. For example, several
they have not followed closely, and practicing physicians different genetic defects can cause peripheral neuropathies,
who remain vitally interested in learning about the remark but disruption oft he normal folding ofm yelin sheaths appears
able changes in molecular medicine. to represent a common final pathway. Likewise, several
Each of the various specialty sections of Principles of genetically distinct forms ofA lzheimer disease appear to share
Molecular Medicine have been edited by experts in their a common final pathway that involves the formation of neu
respective fields. The book opens with a series of introductory rofibrillary tangles. Identification of the nature of the defec
chapters, and each specialty section contains additional back tive genes (e.g., dystrophin, CFTR, FGF-receptor) can
ground overview chapters that address issues of molecular pinpoint the pathway that is involved in key physiologic pro
pathophysiology specific to their respective organ systems. cesses. Similarly, transgenic and gene ''knockout" models can
Even though the field of molecular medicine is evolving reveal the physiologic function of genes.
quickly, the book contains up-to-date reviews oft he genetic basis One of the surprises in this new field of molecular medi
of diseases, with an emphasis on principles that should allow cine is its already pervasive impact in every specialty of
the reader to integrate basic knowledge with all the latest break medicine. For example, cardiologists are unraveling the
throughs. Our authors have aspired to clarify complex topics molecular basis ofinherited cardiomyopathies and ion chan-
vii
viii PREFACE
nel defects that predispose to arrhythmias. Neurologists have We have been fortunate to enlist the expertise of a
identified a startling number of genes in which mutations renowned international group of section editors and authors
lead to neurodegenerative disorders. Not surprisingly, he for Principles ofM olecular Medicine. They have generously
matology has progressed rapidly from the classic genetic taken time from their full palette of research, teaching, and
descriptions ofhemoglobinopathies to define the molecular clinical activities to prepare chapters in a manner that is
basis of other disorders, including red cell membrane useful to individuals both within and outside of their spe
defects, clotting disorders, and thrombotic disorders. The cialty areas. Although the book contains more than 120 chap
genetic causes of leukemias and lymphomas have created ters, it is not all-inclusive. Rather, we have focused on
important paradigms for understanding mechanisms of neo disorders in which there has been substantial recent progress
plasia. The identification of the cystic fibrosis transporter and for which there appear to be gaps in coverage elsewhere.
allows molecular diagnosis oft his disease, and gene therapy The reader is encouraged to seek out further sources for
protocols are underway at several centers. Inherited varia additional information. A particularly valuable resource is
tions in the immune system impact upon susceptibility to the on-line version of Mendelian Inheritance of Man
infectious agents, as well as an array of inflammatory and (OMIM), which can be accessed at www3.ncbi.nlm.hih.gov./
autoimmune disorders. Our understanding of such viral in OMIM. The molecular basis ofm etabolic disorders has been
fections as hepatitis and HIV has been aided greatly by the well-covered in textbooks of internal medicine and in
use ofr ecombinant DNA technology. In endocrinology, new Scriver's, The Metabolic and Molecular Basis ofI nherited
insights into hormone action, sexual differentiation, and Disease. We anticipate that Principles ofM olecular Medi
mechanisms of endocrine neoplasia have been gained by cine will evolve with the field, retaining an emphasis on clini
elucidating the nature ofg enetic defects. Moreover, the field cal molecular medicine.
of hormone and signal transduction has revealed a remark In addition to the dedication and scholarship of our sec
ably intricate network of interacting pathways that mediate tion editors and authors, a great many individuals have con
cellular responses to external signals. In nephrology, a cause tributed to the success ofthis book. The idea for the text was
of polycystic kidney disease has been identified and conceived in discussions with Victoria Reeders. Mary Kay
the molecular pathogenesis of ischemic and inflammatory McMahon provided enormous effort toward the timely
disorders are becoming clearer. In dermatology, there has completion of this projc;ct, superimposed upon her
been remarkable progress in mechanisms of neoplasia, th~ many other responsibilities. Kristina Stanfield, Patty Kalan,
molecular pathogenesis of pemphigoid diseases, and a vari Joanne McAndrews, and William Lowe helped to ensure
ety of other autoimmune disorders. Psychiatry too is an area that last-minute updates were included. I am also grateful to
in which the role of genetics is rapidly emerging as highly the many colleagues who took the time to proofread and
important; the foundations for this development are outlined critique chapters. Many thanks are owed to Thomas Lanigan
in our chapters on behavior, schizophrenia, affective disor at Humana Press for his enthusiastic support and for usher
ders, and alcoholism. Molecular mechanisms have also now ing this concept to completion. I am grateful to many men
been elucidated for many "classic" genetic disorders. Stud tors and students for stimulating my interest in molecular
ies of Prader-Willi, Angelman, and Beckwith-Wiedemann medicine. Among these individuals, I especially acknowl
syndromes have revealed a critical role for imprinting. The edge Joel Habener and William Crowley, with whom I have
impact of nucleotide repeat disorders has been documented in shared the excitement that comes with new insight and dis
the fragile X syndrome, as well as for such neurologic disorders covery. On a personal note, my wife, Michele, and my
as Huntington disease. In most cases, our new knowledge of children, Ryan, Christina, and Jimmy, provided the encour
these disorders has improved the feasibility and accuracy of agement that has allowed me to work in the mode of a
diagnostic testing, enhanced our understanding of pathophysi perpetual student.
ology, and is beginning to unmask new avenues for therapy,
including gene therapy. J. Larry Jameson
Contents
FOREWORD v 12 Congenital Heart Disease 117
Alvin J. Chin
PREFACE VII
13 Inherited Cardiomyopathies 127
CONTRIBUTORS XIV
Christine E. Seidman, Calum MacRae,
LIST OF COLOR PLATES XIX and J. G. Seidman
14 Coronary Atherosclerosis 133
I. INTRODUCTION TO MOLECULAR Robert E. Gerszten and Anthony Rosenzweig
MEDICINE 15 Endothelium-Derived Nitric Oxide
ANDREA BALLAB/0 AND }. LARRY jAMESON and Control of Vascular Tone 141
1 Organization of the Human Genome, Santiago Lamas and Thomas Michel
Chromosomes, and Genes 3 16 Hypertension 145
Sarah H. Elsea and Pragna I. Patel George Koike and Howard J. Jacob
2 Recombinant DNA and Genetic Techniques 9 17 Cardiac Arrhythmias 157
Marcus Grompe, Wade Johnson, Barry London
and J. Larry Jameson 18 Cardiovascular Gene Therapy 161
3 Transcriptional Control of Gene Expression 25 Giuseppe Vassalli and David A. Dichek
Wade Johnson and J. Larry Jameson
4 Transmission of Human Genetic Disease 43 Ill. HEMATOLOGY
Peter Kopp and J. Larry Jameson SWEE LAY THEIN
5 The Human Genome Project 59 19 Hematopoiesis: Growth Factors
J. Larry Jameson and Mechanisms ofR egulation 171
6 The Cell Cycle 65 Andrew Haynes and Nigel Russell
Lynda Q. Nguyen and J. Larry Jameson 20 Disorders of Hemoglobin Structure
7 Oncogenes and Tumor Suppressor Genes 73 and Synthesis 179
Swee Lay Thein and Jacques Rochette
J. Larry Jameson
8 Molecular Diagnostic Testing 83 21 Disorders of the Red Cell Membrane 191
Jean Delaunay
C. Sue Richards and Patricia A. Ward
9 Genetic Counseling 89 22 Red Cell Enzymopathies 197
Lucio Luzzatto and Rosario Notaro
Beth A. Fine
10 Transgenic Mice as Models of Disease 97 23 Coagulation Disorders 209
Martina Daly, Anne Goodeve, Peter Winship,
T. Rajendra Kumar and Martin M. Matzuk
and Ian Peake
24 Thrombotic Disorders 219
II. CARDIOLOGY
Robin J. 0/ds, David A. Lane,
ANTHONY ROSENZWEIG and Swee Lay Thein
11 Molecular Cardiology: An Overview 113 25 Paroxysmal Nocturnal Hemoglobinuria 227
Anthony Rosenzweig Bruno Rotoli and Khedoudja Naja
ix
X CONTENTS
26 Leukemias 233 43 Viral Hepatitis and Liver Disease 387
Jeffrey E. Rubnitz and Ching-Hon Pui Sanjeev Gupta and Michael Ott
27. Lymphomas 241 44 Pancreatic Exocrine Dysfunction 401
Finbarr E. Cotter David Whitcomb and Jonathan Cohn
45 Small- and Large-Bowel Dysfunction 407
IV. IMMUNOLOGY Deborah C. Rubin
RALPH C. WILLIAMS, }R.
28 Regulation of Humoral Immunity 251 VII. ENDOCRINOLOGY
Ralph C. Williams, Jr. MICHAEL }. MCPHAUL
29 Molecular Regulation of Cellular AND }. LARRY jAMESON
Immunity 259 46 Mechanisms of Hormone Action 419
Eric Sobel William L. Lowe, Jr., Richard G. Pestell,
30 Cytokines 267 Laird D. Madison, and J. Larry Jameson
William L. Lowe, Jr., and Barbara A. da Silva 47 Diabetes Mellitus 433
31 The HLA Complex 273 William L. Lowe, Jr.
Robert W. Karr 48 Pituitary Function and Neoplasia 443
32 Inherited Immune Deficiency 283 Shlomo Melmed
Richard Hong 49 Growth Hormone Deficiency Disorders 451
33 Human Immunodeficiency Virus and Acquired Joy D. Cogan and John A. Phillips III
Immune Deficiency Syndrome (AIDS) 293 50 Thyroid Disorders 459
John W. Sleasman and Maureen M Goodenow Peter Kopp and J. Larry Jameson
34 Autoimmune Diseases 299 51 Disorders of the Parathyroid Gland 475
N. Lawrence Edwards Andrew Arnold and Andrew F. Stewart
35 Allergic Diseases: Asthma as a Model 309 52 Congenital Adrenal Hyperplasia 481
Susan M MacDonald Robert C. Wilson and Maria I. New
53 Adrenal Diseases 495
V. PULMONOLOGY Constantine A. Stratakis and George P. Chrousos
MICHAEL }. HOLTZMAN 54 Multiple Endocrine Neoplasia Type 2 505
36 Asthma 319 Robert F. Gagel, Sarah Shefelbine,
and Gilbert Cote
Michael J. Holtzman, Dwight C. Look,
Michael F. /ademarco, Douglas C. Dean, 55 Molecular Mechanisms of Hypoglycemia
Deepak Sampath, and Mario Castro Associated with Increased Insulin
37 Cystic Fibrosis 329 Production 513
Daniel B. Rosenbluth and Steven L. Brody Pamela M Thomas, Gilbert J. Cote,
and Robert F. Gagel
38 Pulmonary Emphysema 339
Steven D. Shapiro and Robert M Senior 56 Regulation of Reproduction 519
Michael J. McPhaul
39 Surfactant Deficiency 349
Jeffrey A. Whitsett and Timothy E. Weaver 57 Disorders of Sex Determination
and Differentiation 527
40 Lung Cancer: The Role of Tumor Suppressor
Genes 357 Charmian A. Quigley
Steven Jay Weintraub 58 Sex Chromosome Disorders 561
Andrew R. Zinn
VI. GASTROENTEROLOGY 59 Disorders of Pubertal Development 569
Karen D. Bradshaw and Charmian A. Quigley
}AMES C. REYNOLDS
41 Hepatology 365 60 Defects of Androgen Action 581
Piet C. de Groen and Nicholas F. LaRusso Michael J. McPhaul
42 Inherited Liver Disease 375 61 Testicular Diseases 587
Juan Ruiz and George Y. Wu Marco Marcelli