Lifton / Somlo / Giebisch Genetic Diseases of the Kidney

1. Auflage 2009
ISBN: 978-0-08-092427-4
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, 848 Seiten

Genetic approaches have revolutionized our understanding of the fundamental causes of human disease by permitting the identification of specific genes in which variation causes or contributes to susceptibility to, or protection from, disease. More than 2,000 disease genes have been identified in the last 20 years, providing important new insight into the pathophysiology of diseases in every field of medicine. Genetic Diseases of the Kidney offers expert insight into the role of genetic abnormalities in the pathogenesis of abnormal kidney function and kidney disease. Genetic abnormalities are carefully presented within the appropriate physiologic context so that readers will understand not only which genes are linked to which diseases but also which pathways lead from a genetic 'disturbance to the systemic appearance of disease. - Lays the essential foundation of mammalian genetics principles for medical professionals with little or no background in genetics - Analyzes specific renal diseases - both monogenic disorders confined to the kidney and systemic diseases with renal involvement - and explains their genetic causes - World-renowned editors and authors offer expert frameworks for understanding the links between genes and complex clinical disorders (i.e., lupus, diabetes, HIV, and hypertension)

Autoren/Hrsg.

Lifton, Richard P.

Somlo, Stefan

Giebisch, Gerhard H.

Seldin, Donald W.

Inhaltsverzeichnis

1;Front Cover;1
2;Genetic Diseases of the Kidney;4
3;Copyright Page;5
4;Contents;6
5;Contributors;10
6;Preface;14
7;PART I: General Background;16
7.1;CHAPTER 1 Genetic Approaches to Human Disease;18
7.1.1;INTRODUCTION;18
7.1.2;BRIEF HISTORY OF GENETICS;18
7.1.3;TRANSMISSION OF SINGLE-GENE DISEASES IN HUMANS;21
7.1.4;NON-MENDELIAN OR COMPLEX TRAITS;24
7.1.5;THE HUMAN GENOME;25
7.1.6;NATURE OF MUTATIONS;25
7.1.7;CONSEQUENCES OF MUTATIONS;26
7.1.8;IDENTIFYING DISEASE-CAUSING MUTATIONS;27
7.1.9;MAPPING MENDELIAN TRAITS IN HUMAN PEDIGREES;28
7.1.10;IDENTIFICATION OF COMMON ALLELES THAT CONTRIBUTE TO COMPLEX TRAITS;33
7.1.11;PERSPECTIVES ON THE FUTURE OF HUMAN DISEASE GENETICS;36
7.1.12;SUMMARY AND PERSPECTIVE;37
7.1.13;REFERENCES;37
7.2;CHAPTER 2 Clinical Applications of Genetics;40
7.2.1;BASIC PRINCIPLES OF GENETIC TESTING;40
7.2.2;SERVICES OFFERED BY GENETIC LABORATORIES;41
7.2.3;COUNSELING AND INFORMED CONSENT;41
7.2.4;ETHICAL CONSIDERATIONS IN GENETIC TESTING;42
7.2.5;CURRENT APPLICATIONS OF GENETIC TESTING;42
7.2.6;MOLECULAR ANALYSES: CURRENT APPROACHES, NEW INNOVATIONS, FUTURE DIRECTIONS;47
7.2.7;PHARMOCOGENOMICS;48
7.2.8;SUMMARY;49
7.2.9;REFERENCES;49
8;PART II;52
8.1;A. Primary Genetic Diseases of Nephron Function;52
8.1.1;CHAPTER 3 Logic of the Kidney;54
8.1.1.1;KIDNEY FUNCTION: A SYSTEMS APPROACH;54
8.1.1.2;WALK THROUGH THE NEPHRON;56
8.1.1.3;INTEGRATION OF ANATOMY AND PHYSIOLOGY: REGULATION;75
8.1.1.4;CONCLUSION;85
8.1.1.5;REFERENCES;86
8.2;B. Primary Genetic Diseases of the Glomerulus;90
8.2.1;CHAPTER 4 Alport’s Disease and Thin Basement Membrane Nephropathy;92
8.2.1.1;INTRODUCTION;92
8.2.1.2;RENAL GLOMERULUS;92
8.2.1.3;GLOMERULAR BASEMENT MEMBRANE;93
8.2.1.4;ALPORT’S DISEASE;96
8.2.1.5;THIN BASEMENT MEMBRANE NEPHROPATHY;101
8.2.1.6;CONCLUSIONS;106
8.2.1.7;REFERENCES;106
8.2.2;CHAPTER 5 Idiopathic Nephrotic Syndrome;112
8.2.2.1;INTRODUCTION;112
8.2.2.2;GENETIC DEFECTS OF STRUCTURAL PROTEINS;113
8.2.2.3;GENETIC DEFECTS OF TRANSCRIPTION FACTORS;119
8.2.2.4;SMARCAL1 AND SCHIMKE IMMUNO-OSSEOUS DYSPLASIA;120
8.2.2.5;GENETIC DEFECTS OF METABOLIC GENES;121
8.2.2.6;GALLOWAY-MOWAT SYNDROME;121
8.2.2.7;CONCLUSIONS;122
8.2.2.8;REFERENCES;122
8.2.3;CHAPTER 6 Focal Segmental Glomerulosclerosis;128
8.2.3.1;INTRODUCTION;128
8.2.3.2;THE PODOCYTE;128
8.2.3.3;FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS;130
8.2.3.4;MENDELIAN DISEASE;130
8.2.3.5;RECESSIVE FSGS: NPHS2;130
8.2.3.6;DOMINANT FSGS;132
8.2.3.7;SYNDROMIC FSGS;134
8.2.3.8;MITOCHONDRIAL PATTERNS OF INHERITANCE;134
8.2.3.9;ANIMAL MODELS;135
8.2.3.10;SECONDARY FSGS;136
8.2.3.11;CLINICAL SPECTRUM OF DISEASE;137
8.2.3.12;SPORADIC FSGS;137
8.2.3.13;APPROACH TO THERAPY;137
8.2.3.14;IMPLICATIONS;138
8.2.3.15;REFERENCES;138
8.3;C. Primary Genetic Diseases of the Proximal Renal Tubules;144
8.3.1;CHAPTER 7 Diseases of Renal Glucose Handling;146
8.3.1.1;INTRODUCTION;146
8.3.1.2;PHYSIOLOGY OF RENAL GLUCOSE TRANSPORT;146
8.3.1.3;INHERITED DISORDERS OF RENAL GLUCOSE TRANSPORT;148
8.3.1.4;SUMMARY AND OUTLOOK;153
8.3.1.5;ACKNOWLEDGMENTS;153
8.3.1.6;REFERENCES;153
8.3.2;CHAPTER 8 Primary Inherited Aminoacidurias: Genetic Defects in the Renal Handling of Amino Acids;156
8.3.2.1;PRIMARY INHERITED AMINOACIDURIAS;156
8.3.2.2;DEFECTS ASSOCIATED WITH HETEROMERIC AMINO ACID TRANSPORTERS;157
8.3.2.3;HARTNUP DISORDER;165
8.3.2.4;THE MOLECULAR BASES OF INTESTINAL ABSORPTION AND RENAL REABSORPTION OF AMINO ACIDS;167
8.3.2.5;REFERENCES;170
8.3.3;CHAPTER 9 Primary Renal Uricosuria;176
8.3.3.1;INTRODUCTION;176
8.3.3.2;BASICS OF URATE HANDLING IN HUMAN KIDNEY;176
8.3.3.3;HEREDITARY RENAL HYPOURICEMIA;180
8.3.3.4;REFERENCES;183
8.3.4;CHAPTER 10 The Fanconi Syndrome;186
8.3.4.1;INTRODUCTION;186
8.3.4.2;HISTORY OF THE FANCONI SYNDROME;186
8.3.4.3;ETIOLOGY;187
8.3.4.4;GENETIC CAUSES;188
8.3.4.5;SYSTEMIC AND RENAL DISEASES;190
8.3.4.6;EXOGENOUS SUBSTANCES;190
8.3.4.7;BRIEF OVERVIEW OF PROXIMAL TUBULE TRANSPORT;190
8.3.4.8;CLINICAL PATHOPHYSIOLOGY;191
8.3.4.9;CELLULAR MECHANISMS OF PROXIMAL TUBULE TRANSPORT DEFECTS;196
8.3.4.10;ANIMAL MODELS OF FANCONI SYNDROME;201
8.3.4.11;TREATMENT;203
8.3.4.12;SUMMARY;204
8.3.4.13;REFERENCES;204
8.3.5;CHAPTER 11 Proximal Renal Tubular Acidosis;214
8.3.5.1;INTRODUCTION;214
8.3.5.2;CELLULAR AND MOLECULAR MECHANISMS OF ACID–BASE TRANSPORT IN THE PROXIMAL TUBULE;214
8.3.5.3;DEFINITION AND CLINICAL FEATURES OF PROXIMAL RTA;218
8.3.5.4;SPECIFIC DISORDERS CAUSING PROXIMAL RENAL TUBULAR ACIDOSIS;221
8.3.5.5;TREATMENT;224
8.3.5.6;REFERENCES;224
8.3.6;CHAPTER 12 Dent’s Disease;228
8.3.6.1;INTRODUCTION;228
8.3.6.2;PHYSIOLOGY OF CLC CHLORIDE CHANNELS;228
8.3.6.3;GENETICS;233
8.3.6.4;CLINICAL PHENOTYPE AND PATHOPHYSIOLOGY OF DENT’S DISEASE;234
8.3.6.5;TREATMENT;237
8.3.6.6;REFERENCES;238
8.4;D. Primary Genetic Diseases of the Thick Ascending Limb of Henle;242
8.4.1;CHAPTER 13 Molecular Genetics of Gitelman’s and Bartter’s Syndromes and their Implications for Blood Pressure Variation;244
8.4.1.1;INTRODUCTION;244
8.4.1.2;HISTORY OF BARTTER’S AND GITELMAN’S SYNDROMES;244
8.4.1.3;MUTATIONS IN NCC CAUSE GITELMAN’S SYNDROME;246
8.4.1.4;UNIFORMITY OF ELECTROLYTE PHENOTYPES OF PATIENTS WITH GITELMAN’S SYNDROME;247
8.4.1.5;PATHOPHYSIOLOGY OF GITELMAN’S SYNDROME;248
8.4.1.6;CLINICAL SIGNS AND SYMPTOMS IN GITELMAN’S SYNDROME;249
8.4.1.7;GITELMAN’S SYNDROME PATIENTS HAVE REDUCED BLOOD PRESSURE AND INCREASED DIETARY SALT INTAKE;249
8.4.1.8;GITELMAN’S SYNDROME PATIENTS DISPLAY INCREASED BONE DENSITY;250
8.4.1.9;MUTATIONS IN NKCC2;250
8.4.1.10;MUTATIONS IN ROMK;251
8.4.1.11;MUTATIONS IN CLCNKB;251
8.4.1.12;MUTATIONS IN BARTTIN CAUSE BARTTER’S SYNDROME WITH SENSORINEURAL DEAFNESS;252
8.4.1.13;COMBINED MUTATIONS IN CLCNKA AND CLCNKB CAUSE BARTTER’S SYNDROME WITH SENSORINEURAL DEAFNESS;252
8.4.1.14;MUTATIONS IN THE CALCIUM-SENSING RECEPTOR (CASR);253
8.4.1.15;OTHER GENETIC DISEASES WITH FEATURES THAT OVERLAP WITH GITELMAN’S AND BARTTER’S SYNDROMES;253
8.4.1.16;PATHOPHYSIOLOGY OF BARTTER’S SYNDROME;253
8.4.1.17;GENOTYPE–PHENOTYPE CORRELATIONS (TABLE 13.1) AND DIAGNOSIS;254
8.4.1.18;TREATMENT OF PATIENTS WITH GITELMAN’S AND BARTTER’S SYNDROMES;256
8.4.1.19;EFFECTS OF THE HETEROZYGOUS STATE FOR GITELMAN’S AND BARTTER’S SYNDROMES ON BLOOD PRESSURE IN THE POPULATION;257
8.4.1.20;ACKNOWLEDGMENTS;258
8.4.1.21;REFERENCES;258
8.4.2;CHAPTER 14 Molecular Genetics of Magnesium Homeostasis;264
8.4.2.1;INTRODUCTION;264
8.4.2.2;PHYSIOLOGY OF MAGNESIUM HOMEOSTASIS;264
8.4.2.3;FAMILIAL HYPOMAGNESEMIA WITH HYPERCALCIURIA AND NEPHROCALCINOSIS (FHHNC);266
8.4.2.4;GITELMAN AND BARTTER SYNDROMES;269
8.4.2.5;HYPOMAGNESEMIA WITH SECONDARY HYPOCALCEMIA (HSH);269
8.4.2.6;AUTOSOMAL DOMINANT HYPOMAGNESEMIA DUE TO MUTATION IN FXYD2;271
8.4.2.7;ISOLATED RECESSIVE RENAL HYPOMAGNESEMIA;272
8.4.2.8;CONCLUSIONS AND FUTURE DIRECTIONS;272
8.4.2.9;ACKNOWLEDGMENTS;273
8.4.2.10;REFERENCES;273
8.4.3;CHAPTER 15 Inherited Diseases of the Calcium-Sensing Receptor: Impact on Parathyroid and Renal Function;278
8.4.3.1;INTRODUCTION;278
8.4.3.2;THE CALCIUM-SENSING RECEPTOR;279
8.4.3.3;ROLE OF THE CaR IN THE PARATHYROID;280
8.4.3.4;ROLE OF THE CaR IN THE KIDNEY;280
8.4.3.5;ROLE OF THE CAR IN OTHER TISSUES INVOLVED IN CALCIUM HOMEOSTASIS;281
8.4.3.6;FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH) [OMIM 14598];281
8.4.3.7;NEONATAL SEVERE PRIMARY HYPERPARATHYROIDISM (NSHPT) [OMIM 239200];285
8.4.3.8;AUTOSOMAL DOMINANT HYPOPARATHYROIDISM (ADH) (OMIM) [#601298];287
8.4.3.9;BARTTER’S SYNDROME WITH ACTIVATING CAR MUTATIONS;288
8.4.3.10;CaR-BASED THERAPEUTICS;288
8.4.3.11;SUMMARY AND FUTURE ISSUES;289
8.4.3.12;DEDICATION;289
8.4.3.13;REFERENCES;289
8.5;E. Primary Genetic Diseases of the Distal Convoluted Tubule and Collecting Duct;294
8.5.1;CHAPTER 16 Liddle’s Syndrome (Pseudoaldosteronism);296
8.5.1.1;INTRODUCTION;296
8.5.1.2;PSEUDOALDOSTERONISM;296
8.5.1.3;ENaC AND Na[sup(+)] ABSORPTION IN THE ASDN;297
8.5.1.4;GENOTYPE–PHENOTYPE RELATIONSHIP;298
8.5.1.5;DIFFERENTIAL DIAGNOSIS;299
8.5.1.6;PATHOPHYSIOLOGY;299
8.5.1.7;MUTATIONS OF THE PY MOTIF: A DUAL EFFECT ON ENaC FUNCTION;300
8.5.1.8;PY MOTIFS AND ALDOSTERONE RESPONSE;301
8.5.1.9;MOUSE MODELS OF LIDDLE’S SYNDROME;301
8.5.1.10;PATHOGENESIS;302
8.5.1.11;REFERENCES;303
8.5.2;CHAPTER 17 The Syndrome of Apparent Mineralocorticoid Excess;306
8.5.2.1;CLINICAL FEATURES OF THE SYNDROME OF APPARENT MINERALOCORTICOID EXCESS (AME);306
8.5.2.2;MOLECULAR STUDIES OF 11ß-HYDROXYSTEROID DEHYDROGENASE (11-HSD);308
8.5.2.3;THE HSD11B2 GENE;309
8.5.2.4;MOLECULAR GENETIC ANALYSIS OF APPARENT MINERALOCORTICOID EXCESS;310
8.5.2.5;REFERENCES;313
8.5.3;CHAPTER 18 Pseudohypaldosteronism Type 1 and Hypertension Exacerbated in Pregnancy;316
8.5.3.1;MINERALOCORTICOID RECEPTOR MUTATIONS IN HUMAN DISEASE;316
8.5.3.2;ALDOSTERONE BIOLOGY;316
8.5.3.3;PSEUDOHYPOALDOSTERONISM TYPE 1;317
8.5.3.4;ANIMAL MODELS OF PHA1;320
8.5.3.5;HYPERTENSION EXACERBATED BY PREGNANCY;320
8.5.3.6;THE S810L MUTATION ALTERS RECEPTOR SPECIFICITY VIA A NEW INTRAMOLECULAR CONTACT;323
8.5.3.7;GENETICS;324
8.5.3.8;A SPLICING DEFECT IN MR[sub(L810)] CARRIERS;324
8.5.3.9;PERSPECTIVES;325
8.5.3.10;REFERENCES;325
8.5.4;CHAPTER 19 The Syndrome of Hypertension and Hyperkalemia (Pseudohypoaldosteronism Type II): WNK Kinases Regulate the Balance Between Renal Salt Reabsorption and Potassium Secretion;328
8.5.4.1;THE ROLE OF THE KIDNEY IN THE REGULATION OF BLOOD PRESSURE AND ELECTROLYTE HOMEOSTASIS;328
8.5.4.2;PSEUDOHYPOALDOSTERONISM TYPE II: A HUMAN MODEL TO EXPLORE COORDINATED REGULATION OF BLOOD PRESSURE AND ELECTROLYTE HOMEOSTASIS;329
8.5.4.3;HYPOTHESES OF PHAII PATHOPHYSIOLOGY;330
8.5.4.4;MOLECULAR GENETICS OF PSEUDOHYPOALDOSTERONISM TYPE II: EVIDENCE FOR GENETIC HETEROGENEITY AND DISCOVERY OF THE WNK PROTEIN KINASES;331
8.5.4.5;THE WNKs ARE A NOVEL FAMILY OF SALT-SENSITIVE SERINE-THREONINE KINASES WITH A UNIQUE CATALYTIC STRUCTURE;333
8.5.4.6;WNK1 AND WNK4 LOCALIZE TO THE ALDOSTERONE-SENSITIVE DISTAL NEPHRON AND EXTRARENAL CHLORIDE-TRANSPORTING EXTRARENAL EPITHELIA;333
8.5.4.7;WNK1 AND WNK4 REGULATE DIVERSE ALDOSTERONE-SENSITIVE MEDIATORS OF ION TRANSPORT VIA DISTINCT MECHANISMS;334
8.5.4.8;IN VIVO MOUSE MODELS OF WNK1 AND WNK4 FUNCTION;337
8.5.4.9;PATHOPHYSIOLOGICAL MECHANISMS OF PHAII;337
8.5.4.10;POSSIBLE ROLE OF WNK1 AND WNK4 IN ESSENTIAL HYPERTENSION AND WNKs AS POTENTIAL TARGETS OF NOVEL THERAPEUTICS;338
8.5.4.11;THE ROLE OF THE WNK KINASES IN THE REGULATION OF CELL VOLUME AND INTRACELLULAR CHLORIDE HOMEOSTASIS;339
8.5.4.12;VOLUME SENSITIVITY OF CATION/CHLORIDE COTRANSPORTERS IS REGULATED BY AN INTERACTION BETWEEN THE WNK AND STE20-TYPE KINASES SPAK/OSR1;340
8.5.4.13;THE WNK KINASE/STE20-TYPE KINASE/NKCC PHOSPHORYLATION CASCADE;340
8.5.4.14;WNK3: A BRAIN-ENRICHED KINASE WITH RECIPROCAL ACTIONS ON THE NKCCs AND KCCs;340
8.5.4.15;CONCLUSIONS AND FUTURE DIRECTIONS;341
8.5.4.16;ACKNOWLEDGMENTS;342
8.5.4.17;DEDICATION;342
8.5.4.18;REFERENCES;342
8.5.5;CHAPTER 20 Distal Renal Tubular Acidosis;346
8.5.5.1;INTRODUCTION;346
8.5.5.2;DEFINITION AND CLINICAL FEATURES;346
8.5.5.3;a-INTERCALATED CELL FUNCTION;347
8.5.5.4;AUTOSOMAL DOMINANT DISTAL RENAL TUBULAR ACIDOSIS;348
8.5.5.5;AUTOSOMAL RECESSIVE TYPE 1 RTA;350
8.5.5.6;GENOTYPE–PHENOTYPE CORRELATIONS IN PRIMARY DISTAL RTA;351
8.5.5.7;OTHER FORMS OF dRTA;352
8.5.5.8;ACKNOWLEDGMENT;352
8.5.5.9;REFERENCES;352
8.5.6;CHAPTER 21 Nephrogenic Diabetes Insipidus: Vasopressin Receptor Defect;356
8.5.6.1;CELLULAR ACTIONS OF VASOPRESSIN;356
8.5.6.2;RARENESS AND DIVERSITY OF AVPR2 MUTATIONS;357
8.5.6.3;BENEFITS OF GENETIC TESTING;359
8.5.6.4;MOST MUTANT V[sub(2)] RECEPTORS ARE NOT TRANSPORTED TO THE CELL MEMBRANE AND ARE RETAINED IN THE INTRACELLULAR COMPARTMENTS;359
8.5.6.5;NONPEPTIDE VASORESSIN RECEPTOR ANTAGONISTS ACT AS PHARMACOLOGICAL CHAPERONES TO FUNCTIONALLY RESCUE MISFOLDED MUTANT V[sub(2)] RECEPTORS RESPONSIBLE FOR X-LINKED NDI;360
8.5.6.6;TESTING PATIENTS WITH NDI; PLEASE AVOID DEHYDRATION;362
8.5.6.7;ACKNOWLEDGMENTS;362
8.5.6.8;REFERENCES;362
8.5.7;CHAPTER 22 Nephrogenic Diabetes Insipidus: Aquaporin-2 Defect;366
8.5.7.1;INTRODUCTION;366
8.5.7.2;MOLECULAR STRUCTURE OF AQUAPORINS;366
8.5.7.3;AQUAPORIN 2;366
8.5.7.4;HISTORY OF NDI;369
8.5.7.5;THE AQP2 GENE;370
8.5.7.6;TREATMENT FOR NDI;373
8.5.7.7;REFERENCES;374
9;PART III: Genetic Abnormalities of Renal Development and Morphogenesis;378
9.1;CHAPTER 23 An Overview of Renal Development;380
9.1.1;INTRODUCTION;380
9.1.2;ANATOMIC DESCRIPTION OF KIDNEY DEVELOPMENT;381
9.1.3;SPECIFICATION OF THE NEPHRIC (WOLFFIAN) DUCT AND NEPHROGENIC CORD;382
9.1.4;METANEPHRIC KIDNEY DEVELOPMENT;384
9.1.5;CONCLUSION;401
9.1.6;REFERENCES;401
9.2;CHAPTER 24 Polycystic Kidney Disease;408
9.2.1;INTRODUCTION;408
9.2.2;DIAGNOSIS AND CLINICAL FEATURES;408
9.2.3;GENETICS OF POLYCYSTIC KIDNEY DISEASE;413
9.2.4;POLYCYSTIN-1;417
9.2.5;POLYCYSTIN-2;418
9.2.6;POLYDUCTIN/FIBROCYSTIN;419
9.2.7;CILIA;420
9.2.8;POLYCYSTIC KIDNEY DISEASES AND CELLULAR PATHWAYS;422
9.2.9;THERAPY IN PKD;428
9.2.10;REFERENCES;429
9.3;CHAPTER 25 Nephronophthisis;440
9.3.1;OVERVIEW ON NEPHRONOPHTHISIS AND RELATED DISORDERS;440
9.3.2;MODE OF INHERITANCE;440
9.3.3;EPIDEMIOLOGY;440
9.3.4;CLINICAL FEATURES OF NPHP;441
9.3.5;PATHOLOGY;443
9.3.6;MOLECULAR GENETICS OF NPHP: AN ETIOLOGICAL CLASSIFICATION OF NPHP;448
9.3.7;FUNCTION OF NEPHROCYSTINS AND PATHOGENESIS OF NPHP;450
9.3.8;DIAGNOSTICS: MOLECULAR GENETICS, IMAGING, AND LABORATORY STUDIES;454
9.3.9;THERAPY, PROGNOSIS, AND GENETIC COUNSELING;455
9.3.10;REFERENCES;455
9.4;CHAPTER 26 Medullary Cystic Disease;462
9.4.1;INTRODUCTION;462
9.4.2;HISTORY;463
9.4.3;EPIDEMIOLOGY;465
9.4.4;GENETICS;466
9.4.5;PATHOPHYSIOLOGY;468
9.4.6;CLINICAL MANIFESTATIONS;469
9.4.7;PATHOLOGY;471
9.4.8;DIAGNOSIS;471
9.4.9;TREATMENT;472
9.4.10;FUTURE HORIZONS;474
9.4.11;REFERENCES;474
9.5;CHAPTER 27 Renal Dysgenesis;478
9.5.1;INTRODUCTION;478
9.5.2;RENAL DEVELOPMENTAL DEFECTS;478
9.5.3;KIDNEY DEVELOPMENT;480
9.5.4;HUMAN SYNDROMES ASSOCIATED WITH RENAL DYSGENESIS;483
9.5.5;ACKNOWLEDGMENTS;501
9.5.6;REFERENCES;501
10;PART IV: Inherited Neoplastic Diseases Affecting the Kidney;510
10.1;CHAPTER 28 The Genetic Basis of Cancer of the Kidney;512
10.1.1;INTRODUCTION;512
10.1.2;VON HIPPEL-LINDAU DISEASE;512
10.1.3;OTHER MANIFESTATIONS;514
10.1.4;MANAGEMENT OF PATIENTS WITH VHL;515
10.1.5;HEREDITARY PAPILLARY RENAL CELL CANCER;516
10.1.6;BIRT-HOGG-DUBÉ SYNDROME;518
10.1.7;HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CARCINOMA;519
10.1.8;CONCLUSIONS;521
10.1.9;REFERENCES;521
10.2;CHAPTER 29 Wilms’ Tumor;524
10.2.1;INTRODUCTION;524
10.2.2;WILMS’ TUMOR: HISTOLOGY, GENETICS, AND ASSOCIATED SYNDROMES;524
10.2.3;THE WT1 GENE, mRNAS, AND PROTEINS;527
10.2.4;THE ROLE OF WT1(–KTS) VS. WT1(+KTS) ISOFORMS;529
10.2.5;WT1 FUNCTION DURING KIDNEY DEVELOPMENT;531
10.2.6;WT1 IN HUMAN UROGENITAL SYNDROMES;534
10.2.7;(–KTS) AND (+KTS) EXPRESSING MOUSE MODELS OF KIDNEY DISEASE;534
10.2.8;CONCLUSIONS;534
10.2.9;ACKNOWLEDGMENTS;535
10.2.10;REFERENCES;535
10.3;CHAPTER 30 Tuberous Sclerosis;542
10.3.1;INTRODUCTION;542
10.3.2;CLINICAL FEATURES OF TSC;542
10.3.3;CLINICAL AND MOLECULAR GENETICS OF TSC;545
10.3.4;GENOTYPE–PHENOTYPE CORRELATIONS;548
10.3.5;GENETIC COUNSELING IN TSC;550
10.3.6;MOLECULAR PATHOGENESIS OF TUBEROUS SCLEROSIS;550
10.3.7;THERAPIES FOR TSC;554
10.3.8;ACKNOWLEDGMENTS;555
10.3.9;REFERENCES;555
11;PART V: Systemic Diseases with Renal Involvement: Monogenic Disorders;558
11.1;CHAPTER 31 Nail-Patella Syndrome;560
11.1.1;CLINICAL FEATURES AND NATURAL HISTORY;560
11.1.2;ESTABLISHING THE DIAGNOSIS;562
11.1.3;MANAGEMENT, TREATMENT, AND COUNSELING;563
11.1.4;LMX1B: GENE STRUCTURE, MUTATIONS IN NPS AND THEIR PREDICTED EFFECT;563
11.1.5;HISTORY OF THE LMX1B GENE AND ANIMAL MODELS OF NPS AND LMX1B FUNCTION;566
11.1.6;ROLE OF LMX1B DURING KIDNEY DEVELOPMENT;567
11.1.7;PATHOGENESIS OF NPS AND IMPORTANT QUESTIONS;568
11.1.8;ACKNOWLEDGMENTS;569
11.1.9;REFERENCES;569
11.2;CHAPTER 32 Mitochondrial Diseases of the Kidney;574
11.2.1;INTRODUCTION;574
11.2.2;MITOCHONDRIAL GENOME AND GENETICS;574
11.2.3;FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS);575
11.2.4;INTERSTITIAL NEPHRITIS;576
11.2.5;FANCONI’S SYNDROME;577
11.2.6;RHABDOMYOLYSIS;578
11.2.7;ONCOCYTOMA;578
11.2.8;ELECTROLYTE ABNORMALITIES;578
11.2.9;HYPERTENSION;579
11.2.10;TREATMENT;580
11.2.11;GENETIC COUNSELING;581
11.2.12;ACKNOWLEDGMENTS;581
11.2.13;REFERENCES;581
11.3;CHAPTER 33 Primary Hyperoxaluria;586
11.3.1;INTRODUCTION;586
11.3.2;BIOCHEMISTRY;588
11.3.3;GENETICS;590
11.3.4;DIAGNOSIS/SCREENING;593
11.3.5;TREATMENT/MANAGEMENT;596
11.3.6;UNCLASSIFIED HYPEROXALURIA;597
11.3.7;CONCLUSION;598
11.3.8;ACKNOWLEDGMENTS;598
11.3.9;REFERENCES;598
11.4;CHAPTER 34 The Oculocerebrorenal Syndrome of Lowe;602
11.4.1;INTRODUCTION;602
11.4.2;GENETICS;602
11.4.3;FUNCTION OF OCRL1 GENE PRODUCT (ocrl1);603
11.4.4;PHYSICAL FEATURES;604
11.4.5;OPHTHALMOLOGIC ABNORMALITIES;604
11.4.6;NEUROLOGIC MANIFESTATIONS;604
11.4.7;MUSCULOSKELETAL MANIFESTATIONS;605
11.4.8;RENAL MANIFESTATIONS;605
11.4.9;RENAL PATHOLOGY;606
11.4.10;DIAGNOSIS;606
11.4.11;CARRIER DETECTION;606
11.4.12;PRENATAL DIAGNOSIS;608
11.4.13;TREATMENT;608
11.4.14;REFERENCES;609
11.5;CHAPTER 35 Fabry’s Disease (a-Galactosidase A Deficiency): An X-linked Nephropathy;612
11.5.1;INTRODUCTION;612
11.5.2;THE CLASSIC PHENOTYPE;612
11.5.3;HETEROZYGOTES FOR THE CLASSIC PHENOTYPE;616
11.5.4;THE LATER-ONSET VARIANTS;617
11.5.5;PATHOLOGY;618
11.5.6;THE METABOLIC AND MOLECULAR DEFECTS IN FABRY DISEASE;619
11.5.7;DIAGNOSIS;620
11.5.8;TREATMENT;621
11.5.9;ENZYME REPLACEMENT THERAPY;622
11.5.10;FUTURE THERAPIES;625
11.5.11;FUTURE PROSPECTS;627
11.5.12;ACKNOWLEDGMENTS;627
11.5.13;REFERENCES;627
11.6;CHAPTER 36 Hereditary Fructose Intolerance;632
11.6.1;INTRODUCTION;632
11.6.2;HISTORY;632
11.6.3;CLINICAL FEATURES AND PRESENTATION (TABLE 36.1);634
11.6.4;PERILS OF FRUCTOSE POISONING IN THE CLINICAL ENVIRONMENT;636
11.6.5;THE SYNDROME OF CHRONIC FRUCTOSE INTOXICATION;637
11.6.6;EFFECTS OF HEREDITARY FRUCTOSE INTOLERANCE ON THE KIDNEY;637
11.6.7;INHERITANCE OF HEREDITARY FRUCTOSE INTOLERANCE;640
11.6.8;PATHOLOGICAL INJURY IN HEREDITARY FRUCTOSE INTOLERANCE;640
11.6.9;METABOLISM OF FRUCTOSE;641
11.6.10;PRIMARY BIOCHEMICAL DEFECT IN FRUCTOSE INTOLERANCE;642
11.6.11;THE ENZYMATIC DEFECT;643
11.6.12;THE ENVIRONMENTAL FACTOR: FRUCTOSE, A UBIQUITOUS NUTRIENT;644
11.6.13;MOLECULAR PATHOLOGY OF ALDOLASE B DEFICIENCY;645
11.6.14;DIAGNOSIS OF HEREDITARY FRUCTOSE INTOLERANCE;647
11.6.15;TREATMENT AND PROGNOSIS;650
11.6.16;PREVENTION OF FRUCTOSE INTOLERANCE BY GENETIC SCREENING;651
11.6.17;ACKNOWLEDGMENTS;652
11.6.18;REFERENCES;652
11.7;CHAPTER 37 The Branchio-oto-renal Syndrome;658
11.7.1;INTRODUCTION;658
11.7.2;THE BOR PHENOTYPE;658
11.7.3;DIAGNOSIS;660
11.7.4;DIFFERENTIAL DIAGNOSIS;660
11.7.5;THE GENETICS OF BOR SYNDROME;660
11.7.6;REFERENCES;662
11.8;CHAPTER 38 Primary Metabolic and Renal Hyperuricemia;666
11.8.1;INTRODUCTION;666
11.8.2;CLASSIFICATION OF HYPERURICEMIA;668
11.8.3;PURINE METABOLISM;668
11.8.4;SINGLE GENE DISORDER FOR OVERPRODUCTION TYPE HYPERURICEMIA;669
11.8.5;SINGLE GENE DISORDER FOR DECREASED EXCRETION TYPE HYPERURICEMIA;671
11.8.6;REFERENCES;673
11.9;CHAPTER 39 Hereditary Cystinosis;676
11.9.1;INTRODUCTION;676
11.9.2;CLINICAL COURSE;676
11.9.3;METABOLIC DEFECT;677
11.9.4;DIAGNOSIS AND TREATMENT;677
11.9.5;CAUSATIVE GENE AND ENCODED PROTEIN;678
11.9.6;FUNCTION OF CYSTINOSIN;680
11.9.7;CTNS MUTATIONS;681
11.9.8;CYSTINOSIN-DEFICIENT MOUSE MODEL;690
11.9.9;CONCLUSIONS;692
11.9.10;REFERENCES;692
11.10;CHAPTER 40 Hepatorenal Tyrosinemia;696
11.10.1;INTRODUCTION;696
11.10.2;HTI: A SEVERE LIVER AND KIDNEY DISEASE;697
11.10.3;DIAGNOSTIC AND DETECTION OF HEREDITARY TYROSINEMIA;698
11.10.4;TREATMENT FOR HTI;698
11.10.5;MOLECULAR GENETICS OF HTI;698
11.10.6;SITE-SPECIFIC REVERSION OF MUTATIONS IN HTI AND RESTORATION OF ENZYME ACTIVITY;699
11.10.7;ANIMAL MODELS OF HTI;700
11.10.8;GENE AND CELLULAR THERAPY AS POTENTIAL TREATMENTS IN HTI;701
11.10.9;PERSPECTIVES;703
11.10.10;REFERENCES;703
11.11;CHAPTER 41 Renal Disease in Type I Glycogen Storage Disease;708
11.11.1;HISTORICAL BACKGROUND;708
11.11.2;CLINICAL PRESENTATION;708
11.11.3;THE G6Pase COMPLEX AND PATHOPHYSIOLOGY OF GSD-I;710
11.11.4;THE MOLECULAR BASIS OF GSD-Ia;711
11.11.5;THE MOLECULAR BASIS OF GSD-Ib;711
11.11.6;ANIMAL MODELS OF GSD-I;713
11.11.7;KIDNEY DISEASE ASSOCIATED WITH GSD-I;713
11.11.8;RENAL DISEASE IN GSD-I AND DIABETES MELLITUS;717
11.11.9;TREATMENT OF GSD-I;718
11.11.10;CONCLUSIONS;720
11.11.11;REFERENCES;720
11.12;CHAPTER 42 Wilson Disease and the Kidney;724
11.12.1;INTRODUCTION;724
11.12.2;MOLECULAR PATHOPHYSIOLOGY OF WILSON DISEASE;724
11.12.3;RENAL COPPER EXCRETION AND TRANSPORT;725
11.12.4;RENAL TUBULAR INJURY AND OTHER FINDINGS;726
11.12.5;HEPATORENAL SYNDROME;727
11.12.6;INTERVENTIONS FOR WILSON DISEASE;727
11.12.7;DRUG-INDUCED RENAL INJURY;727
11.12.8;CONCLUSION;728
11.12.9;REFERENCES;728
11.13;CHAPTER 43 Genetic Defects in Renal Phosphate Handling;730
11.13.1;INTRODUCTION;730
11.13.2;GENERAL ASPECTS OF RENAL PHOSPHATE HANDLING;730
11.13.3;A MOLECULAR VIEW OF RENAL PHOSPHATE TRANSPORT;732
11.13.4;PRIMARY INHERITED DEFECTS IN RENAL PHOSPHATE HANDING;737
11.13.5;DEFECTS IN RENAL PHOSPHATE HANDLING SECONDARY TO EXTRARENAL INHERITED DEFECTS;738
11.13.6;CONCLUSION AND OUTLOOK;742
11.13.7;ACKNOWLEDGMENTS;743
11.13.8;REFERENCES;744
12;PART VI: Systemic Hereditary Diseases with Renal Involvement: Multifactorial Diseases;750
12.1;CHAPTER 44 Genetic Susceptibility to Kidney Disease a Consequence of Systemic Autoimmunity;752
12.1.1;INTRODUCTION;752
12.1.2;CLINICAL OVERVIEW OF LUPUS NEPHRITIS;752
12.1.3;GENETIC PREDISPOSITION TO SLE;754
12.1.4;PATHOGENESIS OF LUPUS NEPHRITIS;756
12.1.5;NEPHRITIC SUSCEPTIBILITY LOCI MAPPED IN MURINE LUPUS MODELS;757
12.1.6;LUPUS NEPHRITIS LOCI IDENTIFIED IN HUMAN LUPUS;760
12.1.7;CONCLUSION;760
12.1.8;REFERENCES;760
12.2;CHAPTER 45 IgA Nephropathy;764
12.2.1;DEFINITION AND CLINICAL FEATURES;764
12.2.2;PATHOGENESIS;765
12.2.3;GENETIC EPIDEMIOLOGY;769
12.2.4;MOLECULAR GENETICS;774
12.2.5;CONCLUSIONS;778
12.2.6;REFERENCES;778
12.3;CHAPTER 46 Susceptibility to Diabetic Nephropathy;786
12.3.1;OVERVIEW;786
12.3.2;ANIMAL MODELS OF DIABETIC NEPHROPATHY;787
12.3.3;FAMILIAL FACTORS IN DIABETIC NEPHROPATHY;788
12.3.4;CANDIDATE PATHWAYS OF DIABETIC NEPHROPATHY;789
12.3.5;THE SEARCH FOR GENETIC FACTORS IN TYPE 1 DIABETIC NEPHROPATHY;794
12.3.6;THE SEARCH FOR TYPE 2 DIABETIC NEPHROPATHY GENES;795
12.3.7;REFERENCES;799
12.4;CHAPTER 47 HIV-associated Nephropathy;808
12.4.1;INTRODUCTION;808
12.4.2;HISTOLOGY;808
12.4.3;CLINICAL PRESENTATION AND EPIDEMIOLOGY;808
12.4.4;PATHOGENESIS;811
12.4.5;TREATMENT;821
12.4.6;CONCLUSION;825
12.4.7;REFERENCES;826
13;Index;830
13.1;A;830
13.2;B;831
13.3;C;831
13.4;D;832
13.5;E;833
13.6;F;834
13.7;G;834
13.8;H;835
13.9;I;836
13.10;J;837
13.11;K;837
13.12;L;837
13.13;M;838
13.14;N;839
13.15;O;839
13.16;P;840
13.17;R;841
13.18;S;842
13.19;T;842
13.20;U;843
13.21;V;843
13.22;W;843
13.23;X;844
13.24;Z;844
14;Color Plates;846