Genetic Diseases of the Kidney (eBook)

Front Cover 1
Genetic Diseases of the Kidney 4
Copyright Page 5
Contents 6
Contributors 10
Preface 14
PART I: General Background 16
CHAPTER 1 Genetic Approaches to Human Disease 18
INTRODUCTION 18
BRIEF HISTORY OF GENETICS 18
TRANSMISSION OF SINGLE-GENE DISEASES IN HUMANS 21
NON-MENDELIAN OR COMPLEX TRAITS 24
THE HUMAN GENOME 25
NATURE OF MUTATIONS 25
CONSEQUENCES OF MUTATIONS 26
IDENTIFYING DISEASE-CAUSING MUTATIONS 27
MAPPING MENDELIAN TRAITS IN HUMAN PEDIGREES 28
IDENTIFICATION OF COMMON ALLELES THAT CONTRIBUTE TO COMPLEX TRAITS 33
PERSPECTIVES ON THE FUTURE OF HUMAN DISEASE GENETICS 36
SUMMARY AND PERSPECTIVE 37
REFERENCES 37
CHAPTER 2 Clinical Applications of Genetics 40
BASIC PRINCIPLES OF GENETIC TESTING 40
SERVICES OFFERED BY GENETIC LABORATORIES 41
COUNSELING AND INFORMED CONSENT 41
ETHICAL CONSIDERATIONS IN GENETIC TESTING 42
CURRENT APPLICATIONS OF GENETIC TESTING 42
MOLECULAR ANALYSES: CURRENT APPROACHES, NEW INNOVATIONS, FUTURE DIRECTIONS 47
PHARMOCOGENOMICS 48
SUMMARY 49
REFERENCES 49
PART II 52
A. Primary Genetic Diseases of Nephron Function 52
CHAPTER 3 Logic of the Kidney 54
KIDNEY FUNCTION: A SYSTEMS APPROACH 54
WALK THROUGH THE NEPHRON 56
INTEGRATION OF ANATOMY AND PHYSIOLOGY: REGULATION 75
CONCLUSION 85
REFERENCES 86
B. Primary Genetic Diseases of the Glomerulus 90
CHAPTER 4 Alport’s Disease and Thin Basement Membrane Nephropathy 92
INTRODUCTION 92
RENAL GLOMERULUS 92
GLOMERULAR BASEMENT MEMBRANE 93
ALPORT’S DISEASE 96
THIN BASEMENT MEMBRANE NEPHROPATHY 101
CONCLUSIONS 106
REFERENCES 106
CHAPTER 5 Idiopathic Nephrotic Syndrome 112
INTRODUCTION 112
GENETIC DEFECTS OF STRUCTURAL PROTEINS 113
GENETIC DEFECTS OF TRANSCRIPTION FACTORS 119
SMARCAL1 AND SCHIMKE IMMUNO-OSSEOUS DYSPLASIA 120
GENETIC DEFECTS OF METABOLIC GENES 121
GALLOWAY-MOWAT SYNDROME 121
CONCLUSIONS 122
REFERENCES 122
CHAPTER 6 Focal Segmental Glomerulosclerosis 128
INTRODUCTION 128
THE PODOCYTE 128
FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS 130
MENDELIAN DISEASE 130
RECESSIVE FSGS: NPHS2 130
DOMINANT FSGS 132
SYNDROMIC FSGS 134
MITOCHONDRIAL PATTERNS OF INHERITANCE 134
ANIMAL MODELS 135
SECONDARY FSGS 136
CLINICAL SPECTRUM OF DISEASE 137
SPORADIC FSGS 137
APPROACH TO THERAPY 137
IMPLICATIONS 138
REFERENCES 138
C. Primary Genetic Diseases of the Proximal Renal Tubules 144
CHAPTER 7 Diseases of Renal Glucose Handling 146
INTRODUCTION 146
PHYSIOLOGY OF RENAL GLUCOSE TRANSPORT 146
INHERITED DISORDERS OF RENAL GLUCOSE TRANSPORT 148
SUMMARY AND OUTLOOK 153
ACKNOWLEDGMENTS 153
REFERENCES 153
CHAPTER 8 Primary Inherited Aminoacidurias: Genetic Defects in the Renal Handling of Amino Acids 156
PRIMARY INHERITED AMINOACIDURIAS 156
DEFECTS ASSOCIATED WITH HETEROMERIC AMINO ACID TRANSPORTERS 157
HARTNUP DISORDER 165
THE MOLECULAR BASES OF INTESTINAL ABSORPTION AND RENAL REABSORPTION OF AMINO ACIDS 167
REFERENCES 170
CHAPTER 9 Primary Renal Uricosuria 176
INTRODUCTION 176
BASICS OF URATE HANDLING IN HUMAN KIDNEY 176
HEREDITARY RENAL HYPOURICEMIA 180
REFERENCES 183
CHAPTER 10 The Fanconi Syndrome 186
INTRODUCTION 186
HISTORY OF THE FANCONI SYNDROME 186
ETIOLOGY 187
GENETIC CAUSES 188
SYSTEMIC AND RENAL DISEASES 190
EXOGENOUS SUBSTANCES 190
BRIEF OVERVIEW OF PROXIMAL TUBULE TRANSPORT 190
CLINICAL PATHOPHYSIOLOGY 191
CELLULAR MECHANISMS OF PROXIMAL TUBULE TRANSPORT DEFECTS 196
ANIMAL MODELS OF FANCONI SYNDROME 201
TREATMENT 203
SUMMARY 204
REFERENCES 204
CHAPTER 11 Proximal Renal Tubular Acidosis 214
INTRODUCTION 214
CELLULAR AND MOLECULAR MECHANISMS OF ACID–BASE TRANSPORT IN THE PROXIMAL TUBULE 214
DEFINITION AND CLINICAL FEATURES OF PROXIMAL RTA 218
SPECIFIC DISORDERS CAUSING PROXIMAL RENAL TUBULAR ACIDOSIS 221
TREATMENT 224
REFERENCES 224
CHAPTER 12 Dent’s Disease 228
INTRODUCTION 228
PHYSIOLOGY OF CLC CHLORIDE CHANNELS 228
GENETICS 233
CLINICAL PHENOTYPE AND PATHOPHYSIOLOGY OF DENT’S DISEASE 234
TREATMENT 237
REFERENCES 238
D. Primary Genetic Diseases of the Thick Ascending Limb of Henle 242
CHAPTER 13 Molecular Genetics of Gitelman’s and Bartter’s Syndromes and their Implications for Blood Pressure Variation 244
INTRODUCTION 244
HISTORY OF BARTTER’S AND GITELMAN’S SYNDROMES 244
MUTATIONS IN NCC CAUSE GITELMAN’S SYNDROME 246
UNIFORMITY OF ELECTROLYTE PHENOTYPES OF PATIENTS WITH GITELMAN’S SYNDROME 247
PATHOPHYSIOLOGY OF GITELMAN’S SYNDROME 248
CLINICAL SIGNS AND SYMPTOMS IN GITELMAN’S SYNDROME 249
GITELMAN’S SYNDROME PATIENTS HAVE REDUCED BLOOD PRESSURE AND INCREASED DIETARY SALT INTAKE 249
GITELMAN’S SYNDROME PATIENTS DISPLAY INCREASED BONE DENSITY 250
MUTATIONS IN NKCC2 250
MUTATIONS IN ROMK 251
MUTATIONS IN CLCNKB 251
MUTATIONS IN BARTTIN CAUSE BARTTER’S SYNDROME WITH SENSORINEURAL DEAFNESS 252
COMBINED MUTATIONS IN CLCNKA AND CLCNKB CAUSE BARTTER’S SYNDROME WITH SENSORINEURAL DEAFNESS 252
MUTATIONS IN THE CALCIUM-SENSING RECEPTOR (CASR) 253
OTHER GENETIC DISEASES WITH FEATURES THAT OVERLAP WITH GITELMAN’S AND BARTTER’S SYNDROMES 253
PATHOPHYSIOLOGY OF BARTTER’S SYNDROME 253
GENOTYPE–PHENOTYPE CORRELATIONS (TABLE 13.1) AND DIAGNOSIS 254
TREATMENT OF PATIENTS WITH GITELMAN’S AND BARTTER’S SYNDROMES 256
EFFECTS OF THE HETEROZYGOUS STATE FOR GITELMAN’S AND BARTTER’S SYNDROMES ON BLOOD PRESSURE IN THE POPULATION 257
ACKNOWLEDGMENTS 258
REFERENCES 258
CHAPTER 14 Molecular Genetics of Magnesium Homeostasis 264
INTRODUCTION 264
PHYSIOLOGY OF MAGNESIUM HOMEOSTASIS 264
FAMILIAL HYPOMAGNESEMIA WITH HYPERCALCIURIA AND NEPHROCALCINOSIS (FHHNC) 266
GITELMAN AND BARTTER SYNDROMES 269
HYPOMAGNESEMIA WITH SECONDARY HYPOCALCEMIA (HSH) 269
AUTOSOMAL DOMINANT HYPOMAGNESEMIA DUE TO MUTATION IN FXYD2 271
ISOLATED RECESSIVE RENAL HYPOMAGNESEMIA 272
CONCLUSIONS AND FUTURE DIRECTIONS 272
ACKNOWLEDGMENTS 273
REFERENCES 273
CHAPTER 15 Inherited Diseases of the Calcium-Sensing Receptor: Impact on Parathyroid and Renal Function 278
INTRODUCTION 278
THE CALCIUM-SENSING RECEPTOR 279
ROLE OF THE CaR IN THE PARATHYROID 280
ROLE OF THE CaR IN THE KIDNEY 280
ROLE OF THE CAR IN OTHER TISSUES INVOLVED IN CALCIUM HOMEOSTASIS 281
FAMILIAL HYPOCALCIURIC HYPERCALCEMIA (FHH) [OMIM 14598] 281
NEONATAL SEVERE PRIMARY HYPERPARATHYROIDISM (NSHPT) [OMIM 239200] 285
AUTOSOMAL DOMINANT HYPOPARATHYROIDISM (ADH) (OMIM) [#601298] 287
BARTTER’S SYNDROME WITH ACTIVATING CAR MUTATIONS 288
CaR-BASED THERAPEUTICS 288
SUMMARY AND FUTURE ISSUES 289
DEDICATION 289
REFERENCES 289
E. Primary Genetic Diseases of the Distal Convoluted Tubule and Collecting Duct 294
CHAPTER 16 Liddle’s Syndrome (Pseudoaldosteronism) 296
INTRODUCTION 296
PSEUDOALDOSTERONISM 296
ENaC AND Na[sup(+)] ABSORPTION IN THE ASDN 297
GENOTYPE–PHENOTYPE RELATIONSHIP 298
DIFFERENTIAL DIAGNOSIS 299
PATHOPHYSIOLOGY 299
MUTATIONS OF THE PY MOTIF: A DUAL EFFECT ON ENaC FUNCTION 300
PY MOTIFS AND ALDOSTERONE RESPONSE 301
MOUSE MODELS OF LIDDLE’S SYNDROME 301
PATHOGENESIS 302
REFERENCES 303
CHAPTER 17 The Syndrome of Apparent Mineralocorticoid Excess 306
CLINICAL FEATURES OF THE SYNDROME OF APPARENT MINERALOCORTICOID EXCESS (AME) 306
MOLECULAR STUDIES OF 11& #946
THE HSD11B2 GENE 309
MOLECULAR GENETIC ANALYSIS OF APPARENT MINERALOCORTICOID EXCESS 310
REFERENCES 313
CHAPTER 18 Pseudohypaldosteronism Type 1 and Hypertension Exacerbated in Pregnancy 316
MINERALOCORTICOID RECEPTOR MUTATIONS IN HUMAN DISEASE 316
ALDOSTERONE BIOLOGY 316
PSEUDOHYPOALDOSTERONISM TYPE 1 317
ANIMAL MODELS OF PHA1 320
HYPERTENSION EXACERBATED BY PREGNANCY 320
THE S810L MUTATION ALTERS RECEPTOR SPECIFICITY VIA A NEW INTRAMOLECULAR CONTACT 323
GENETICS 324
A SPLICING DEFECT IN MR[sub(L810)] CARRIERS 324
PERSPECTIVES 325
REFERENCES 325
CHAPTER 19 The Syndrome of Hypertension and Hyperkalemia (Pseudohypoaldosteronism Type II): WNK Kinases Regulate the Balance Between Renal Salt Reabsorption and Potassium Secretion 328
THE ROLE OF THE KIDNEY IN THE REGULATION OF BLOOD PRESSURE AND ELECTROLYTE HOMEOSTASIS 328
PSEUDOHYPOALDOSTERONISM TYPE II: A HUMAN MODEL TO EXPLORE COORDINATED REGULATION OF BLOOD PRESSURE AND ELECTROLYTE HOMEOSTASIS 329
HYPOTHESES OF PHAII PATHOPHYSIOLOGY 330
MOLECULAR GENETICS OF PSEUDOHYPOALDOSTERONISM TYPE II: EVIDENCE FOR GENETIC HETEROGENEITY AND DISCOVERY OF THE WNK PROTEIN KINASES 331
THE WNKs ARE A NOVEL FAMILY OF SALT-SENSITIVE SERINE-THREONINE KINASES WITH A UNIQUE CATALYTIC STRUCTURE 333
WNK1 AND WNK4 LOCALIZE TO THE ALDOSTERONE-SENSITIVE DISTAL NEPHRON AND EXTRARENAL CHLORIDE-TRANSPORTING EXTRARENAL EPITHELIA 333
WNK1 AND WNK4 REGULATE DIVERSE ALDOSTERONE-SENSITIVE MEDIATORS OF ION TRANSPORT VIA DISTINCT MECHANISMS 334
IN VIVO MOUSE MODELS OF WNK1 AND WNK4 FUNCTION 337
PATHOPHYSIOLOGICAL MECHANISMS OF PHAII 337
POSSIBLE ROLE OF WNK1 AND WNK4 IN ESSENTIAL HYPERTENSION AND WNKs AS POTENTIAL TARGETS OF NOVEL THERAPEUTICS 338
THE ROLE OF THE WNK KINASES IN THE REGULATION OF CELL VOLUME AND INTRACELLULAR CHLORIDE HOMEOSTASIS 339
VOLUME SENSITIVITY OF CATION/CHLORIDE COTRANSPORTERS IS REGULATED BY AN INTERACTION BETWEEN THE WNK AND STE20-TYPE KINASES SPAK/OSR1 340
THE WNK KINASE/STE20-TYPE KINASE/NKCC PHOSPHORYLATION CASCADE 340
WNK3: A BRAIN-ENRICHED KINASE WITH RECIPROCAL ACTIONS ON THE NKCCs AND KCCs 340
CONCLUSIONS AND FUTURE DIRECTIONS 341
ACKNOWLEDGMENTS 342
DEDICATION 342
REFERENCES 342
CHAPTER 20 Distal Renal Tubular Acidosis 346
INTRODUCTION 346
DEFINITION AND CLINICAL FEATURES 346
& #945
AUTOSOMAL DOMINANT DISTAL RENAL TUBULAR ACIDOSIS 348
AUTOSOMAL RECESSIVE TYPE 1 RTA 350
GENOTYPE–PHENOTYPE CORRELATIONS IN PRIMARY DISTAL RTA 351
OTHER FORMS OF dRTA 352
ACKNOWLEDGMENT 352
REFERENCES 352
CHAPTER 21 Nephrogenic Diabetes Insipidus: Vasopressin Receptor Defect 356
CELLULAR ACTIONS OF VASOPRESSIN 356
RARENESS AND DIVERSITY OF AVPR2 MUTATIONS 357
BENEFITS OF GENETIC TESTING 359
MOST MUTANT V[sub(2)] RECEPTORS ARE NOT TRANSPORTED TO THE CELL MEMBRANE AND ARE RETAINED IN THE INTRACELLULAR COMPARTMENTS 359
NONPEPTIDE VASORESSIN RECEPTOR ANTAGONISTS ACT AS PHARMACOLOGICAL CHAPERONES TO FUNCTIONALLY RESCUE MISFOLDED MUTANT V[sub(2)] RECEPTORS RESPONSIBLE FOR X-LINKED NDI 360
TESTING PATIENTS WITH NDI PLEASE AVOID DEHYDRATION
ACKNOWLEDGMENTS 362
REFERENCES 362
CHAPTER 22 Nephrogenic Diabetes Insipidus: Aquaporin-2 Defect 366
INTRODUCTION 366
MOLECULAR STRUCTURE OF AQUAPORINS 366
AQUAPORIN 2 366
HISTORY OF NDI 369
THE AQP2 GENE 370
TREATMENT FOR NDI 373
REFERENCES 374
PART III: Genetic Abnormalities of Renal Development and Morphogenesis 378
CHAPTER 23 An Overview of Renal Development 380
INTRODUCTION 380
ANATOMIC DESCRIPTION OF KIDNEY DEVELOPMENT 381
SPECIFICATION OF THE NEPHRIC (WOLFFIAN) DUCT AND NEPHROGENIC CORD 382
METANEPHRIC KIDNEY DEVELOPMENT 384
CONCLUSION 401
REFERENCES 401
CHAPTER 24 Polycystic Kidney Disease 408
INTRODUCTION 408
DIAGNOSIS AND CLINICAL FEATURES 408
GENETICS OF POLYCYSTIC KIDNEY DISEASE 413
POLYCYSTIN-1 417
POLYCYSTIN-2 418
POLYDUCTIN/FIBROCYSTIN 419
CILIA 420
POLYCYSTIC KIDNEY DISEASES AND CELLULAR PATHWAYS 422
THERAPY IN PKD 428
REFERENCES 429
CHAPTER 25 Nephronophthisis 440
OVERVIEW ON NEPHRONOPHTHISIS AND RELATED DISORDERS 440
MODE OF INHERITANCE 440
EPIDEMIOLOGY 440
CLINICAL FEATURES OF NPHP 441
PATHOLOGY 443
MOLECULAR GENETICS OF NPHP: AN ETIOLOGICAL CLASSIFICATION OF NPHP 448
FUNCTION OF NEPHROCYSTINS AND PATHOGENESIS OF NPHP 450
DIAGNOSTICS: MOLECULAR GENETICS, IMAGING, AND LABORATORY STUDIES 454
THERAPY, PROGNOSIS, AND GENETIC COUNSELING 455
REFERENCES 455
CHAPTER 26 Medullary Cystic Disease 462
INTRODUCTION 462
HISTORY 463
EPIDEMIOLOGY 465
GENETICS 466
PATHOPHYSIOLOGY 468
CLINICAL MANIFESTATIONS 469
PATHOLOGY 471
DIAGNOSIS 471
TREATMENT 472
FUTURE HORIZONS 474
REFERENCES 474
CHAPTER 27 Renal Dysgenesis 478
INTRODUCTION 478
RENAL DEVELOPMENTAL DEFECTS 478
KIDNEY DEVELOPMENT 480
HUMAN SYNDROMES ASSOCIATED WITH RENAL DYSGENESIS 483
ACKNOWLEDGMENTS 501
REFERENCES 501
PART IV: Inherited Neoplastic Diseases Affecting the Kidney 510
CHAPTER 28 The Genetic Basis of Cancer of the Kidney 512
INTRODUCTION 512
VON HIPPEL-LINDAU DISEASE 512
OTHER MANIFESTATIONS 514
MANAGEMENT OF PATIENTS WITH VHL 515
HEREDITARY PAPILLARY RENAL CELL CANCER 516
BIRT-HOGG-DUBÉ SYNDROME 518
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CARCINOMA 519
CONCLUSIONS 521
REFERENCES 521
CHAPTER 29 Wilms’ Tumor 524
INTRODUCTION 524
WILMS’ TUMOR: HISTOLOGY, GENETICS, AND ASSOCIATED SYNDROMES 524
THE WT1 GENE, mRNAS, AND PROTEINS 527
THE ROLE OF WT1(–KTS) VS. WT1(+KTS) ISOFORMS 529
WT1 FUNCTION DURING KIDNEY DEVELOPMENT 531
WT1 IN HUMAN UROGENITAL SYNDROMES 534
(–KTS) AND (+KTS) EXPRESSING MOUSE MODELS OF KIDNEY DISEASE 534
CONCLUSIONS 534
ACKNOWLEDGMENTS 535
REFERENCES 535
CHAPTER 30 Tuberous Sclerosis 542
INTRODUCTION 542
CLINICAL FEATURES OF TSC 542
CLINICAL AND MOLECULAR GENETICS OF TSC 545
GENOTYPE–PHENOTYPE CORRELATIONS 548
GENETIC COUNSELING IN TSC 550
MOLECULAR PATHOGENESIS OF TUBEROUS SCLEROSIS 550
THERAPIES FOR TSC 554
ACKNOWLEDGMENTS 555
REFERENCES 555
PART V: Systemic Diseases with Renal Involvement: Monogenic Disorders 558
CHAPTER 31 Nail-Patella Syndrome 560
CLINICAL FEATURES AND NATURAL HISTORY 560
ESTABLISHING THE DIAGNOSIS 562
MANAGEMENT, TREATMENT, AND COUNSELING 563
LMX1B: GENE STRUCTURE, MUTATIONS IN NPS AND THEIR PREDICTED EFFECT 563
HISTORY OF THE LMX1B GENE AND ANIMAL MODELS OF NPS AND LMX1B FUNCTION 566
ROLE OF LMX1B DURING KIDNEY DEVELOPMENT 567
PATHOGENESIS OF NPS AND IMPORTANT QUESTIONS 568
ACKNOWLEDGMENTS 569
REFERENCES 569
CHAPTER 32 Mitochondrial Diseases of the Kidney 574
INTRODUCTION 574
MITOCHONDRIAL GENOME AND GENETICS 574
FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) 575
INTERSTITIAL NEPHRITIS 576
FANCONI’S SYNDROME 577
RHABDOMYOLYSIS 578
ONCOCYTOMA 578
ELECTROLYTE ABNORMALITIES 578
HYPERTENSION 579
TREATMENT 580
GENETIC COUNSELING 581
ACKNOWLEDGMENTS 581
REFERENCES 581
CHAPTER 33 Primary Hyperoxaluria 586
INTRODUCTION 586
BIOCHEMISTRY 588
GENETICS 590
DIAGNOSIS/SCREENING 593
TREATMENT/MANAGEMENT 596
UNCLASSIFIED HYPEROXALURIA 597
CONCLUSION 598
ACKNOWLEDGMENTS 598
REFERENCES 598
CHAPTER 34 The Oculocerebrorenal Syndrome of Lowe 602
INTRODUCTION 602
GENETICS 602
FUNCTION OF OCRL1 GENE PRODUCT (ocrl1) 603
PHYSICAL FEATURES 604
OPHTHALMOLOGIC ABNORMALITIES 604
NEUROLOGIC MANIFESTATIONS 604
MUSCULOSKELETAL MANIFESTATIONS 605
RENAL MANIFESTATIONS 605
RENAL PATHOLOGY 606
DIAGNOSIS 606
CARRIER DETECTION 606
PRENATAL DIAGNOSIS 608
TREATMENT 608
REFERENCES 609
CHAPTER 35 Fabry’s Disease (& #945
INTRODUCTION 612
THE CLASSIC PHENOTYPE 612
HETEROZYGOTES FOR THE CLASSIC PHENOTYPE 616
THE LATER-ONSET VARIANTS 617
PATHOLOGY 618
THE METABOLIC AND MOLECULAR DEFECTS IN FABRY DISEASE 619
DIAGNOSIS 620
TREATMENT 621
ENZYME REPLACEMENT THERAPY 622
FUTURE THERAPIES 625
FUTURE PROSPECTS 627
ACKNOWLEDGMENTS 627
REFERENCES 627
CHAPTER 36 Hereditary Fructose Intolerance 632
INTRODUCTION 632
HISTORY 632
CLINICAL FEATURES AND PRESENTATION (TABLE 36.1) 634
PERILS OF FRUCTOSE POISONING IN THE CLINICAL ENVIRONMENT 636
THE SYNDROME OF CHRONIC FRUCTOSE INTOXICATION 637
EFFECTS OF HEREDITARY FRUCTOSE INTOLERANCE ON THE KIDNEY 637
INHERITANCE OF HEREDITARY FRUCTOSE INTOLERANCE 640
PATHOLOGICAL INJURY IN HEREDITARY FRUCTOSE INTOLERANCE 640
METABOLISM OF FRUCTOSE 641
PRIMARY BIOCHEMICAL DEFECT IN FRUCTOSE INTOLERANCE 642
THE ENZYMATIC DEFECT 643
THE ENVIRONMENTAL FACTOR: FRUCTOSE, A UBIQUITOUS NUTRIENT 644
MOLECULAR PATHOLOGY OF ALDOLASE B DEFICIENCY 645
DIAGNOSIS OF HEREDITARY FRUCTOSE INTOLERANCE 647
TREATMENT AND PROGNOSIS 650
PREVENTION OF FRUCTOSE INTOLERANCE BY GENETIC SCREENING 651
ACKNOWLEDGMENTS 652
REFERENCES 652
CHAPTER 37 The Branchio-oto-renal Syndrome 658
INTRODUCTION 658
THE BOR PHENOTYPE 658
DIAGNOSIS 660
DIFFERENTIAL DIAGNOSIS 660
THE GENETICS OF BOR SYNDROME 660
REFERENCES 662
CHAPTER 38 Primary Metabolic and Renal Hyperuricemia 666
INTRODUCTION 666
CLASSIFICATION OF HYPERURICEMIA 668
PURINE METABOLISM 668
SINGLE GENE DISORDER FOR OVERPRODUCTION TYPE HYPERURICEMIA 669
SINGLE GENE DISORDER FOR DECREASED EXCRETION TYPE HYPERURICEMIA 671
REFERENCES 673
CHAPTER 39 Hereditary Cystinosis 676
INTRODUCTION 676
CLINICAL COURSE 676
METABOLIC DEFECT 677
DIAGNOSIS AND TREATMENT 677
CAUSATIVE GENE AND ENCODED PROTEIN 678
FUNCTION OF CYSTINOSIN 680
CTNS MUTATIONS 681
CYSTINOSIN-DEFICIENT MOUSE MODEL 690
CONCLUSIONS 692
REFERENCES 692
CHAPTER 40 Hepatorenal Tyrosinemia 696
INTRODUCTION 696
HTI: A SEVERE LIVER AND KIDNEY DISEASE 697
DIAGNOSTIC AND DETECTION OF HEREDITARY TYROSINEMIA 698
TREATMENT FOR HTI 698
MOLECULAR GENETICS OF HTI 698
SITE-SPECIFIC REVERSION OF MUTATIONS IN HTI AND RESTORATION OF ENZYME ACTIVITY 699
ANIMAL MODELS OF HTI 700
GENE AND CELLULAR THERAPY AS POTENTIAL TREATMENTS IN HTI 701
PERSPECTIVES 703
REFERENCES 703
CHAPTER 41 Renal Disease in Type I Glycogen Storage Disease 708
HISTORICAL BACKGROUND 708
CLINICAL PRESENTATION 708
THE G6Pase COMPLEX AND PATHOPHYSIOLOGY OF GSD-I 710
THE MOLECULAR BASIS OF GSD-Ia 711
THE MOLECULAR BASIS OF GSD-Ib 711
ANIMAL MODELS OF GSD-I 713
KIDNEY DISEASE ASSOCIATED WITH GSD-I 713
RENAL DISEASE IN GSD-I AND DIABETES MELLITUS 717
TREATMENT OF GSD-I 718
CONCLUSIONS 720
REFERENCES 720
CHAPTER 42 Wilson Disease and the Kidney 724
INTRODUCTION 724
MOLECULAR PATHOPHYSIOLOGY OF WILSON DISEASE 724
RENAL COPPER EXCRETION AND TRANSPORT 725
RENAL TUBULAR INJURY AND OTHER FINDINGS 726
HEPATORENAL SYNDROME 727
INTERVENTIONS FOR WILSON DISEASE 727
DRUG-INDUCED RENAL INJURY 727
CONCLUSION 728
REFERENCES 728
CHAPTER 43 Genetic Defects in Renal Phosphate Handling 730
INTRODUCTION 730
GENERAL ASPECTS OF RENAL PHOSPHATE HANDLING 730
A MOLECULAR VIEW OF RENAL PHOSPHATE TRANSPORT 732
PRIMARY INHERITED DEFECTS IN RENAL PHOSPHATE HANDING 737
DEFECTS IN RENAL PHOSPHATE HANDLING SECONDARY TO EXTRARENAL INHERITED DEFECTS 738
CONCLUSION AND OUTLOOK 742
ACKNOWLEDGMENTS 743
REFERENCES 744
PART VI: Systemic Hereditary Diseases with Renal Involvement: Multifactorial Diseases 750
CHAPTER 44 Genetic Susceptibility to Kidney Disease a Consequence of Systemic Autoimmunity 752
INTRODUCTION 752
CLINICAL OVERVIEW OF LUPUS NEPHRITIS 752
GENETIC PREDISPOSITION TO SLE 754
PATHOGENESIS OF LUPUS NEPHRITIS 756
NEPHRITIC SUSCEPTIBILITY LOCI MAPPED IN MURINE LUPUS MODELS 757
LUPUS NEPHRITIS LOCI IDENTIFIED IN HUMAN LUPUS 760
CONCLUSION 760
REFERENCES 760
CHAPTER 45 IgA Nephropathy 764
DEFINITION AND CLINICAL FEATURES 764
PATHOGENESIS 765
GENETIC EPIDEMIOLOGY 769
MOLECULAR GENETICS 774
CONCLUSIONS 778
REFERENCES 778
CHAPTER 46 Susceptibility to Diabetic Nephropathy 786
OVERVIEW 786
ANIMAL MODELS OF DIABETIC NEPHROPATHY 787
FAMILIAL FACTORS IN DIABETIC NEPHROPATHY 788
CANDIDATE PATHWAYS OF DIABETIC NEPHROPATHY 789
THE SEARCH FOR GENETIC FACTORS IN TYPE 1 DIABETIC NEPHROPATHY 794
THE SEARCH FOR TYPE 2 DIABETIC NEPHROPATHY GENES 795
REFERENCES 799
CHAPTER 47 HIV-associated Nephropathy 808
INTRODUCTION 808
HISTOLOGY 808
CLINICAL PRESENTATION AND EPIDEMIOLOGY 808
PATHOGENESIS 811
TREATMENT 821
CONCLUSION 825
REFERENCES 826
Index 830
A 830
B 831
C 831
D 832
E 833
F 834
G 834
H 835
I 836
J 837
K 837
L 837
M 838
N 839
O 839
P 840
R 841
S 842
T 842
U 843
V 843
W 843
X 844
Z 844
Color Plates 846