Suchen und Finden
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 11β-HYDROXYSTEROID DEHYDROGENASE (11-HSD)
308
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
α-INTERCALATED CELL FUNCTION
347
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
362
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 (α-Galactosidase A Deficiency): An X-linked Nephropathy
612
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
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