Genetic Diseases of the Kidney

Cover Page......Page 1
Copyright......Page 2
Dedication......Page 3
Contributors......Page 4
Preface......Page 7
Part I: General Background......Page 9
Brief history of genetics......Page 10
Transmission of single-gene diseases in humans......Page 13
Non-mendelian or complex traits......Page 16
Nature of mutations......Page 17
Consequences of mutations......Page 18
Identifying disease-causing mutations......Page 19
Mapping mendelian traits in human pedigrees......Page 20
Identification of common alleles that contribute to complex traits......Page 25
Perspectives on the future of human disease genetics......Page 28
References......Page 29
Basic principles of genetic testing......Page 32
Counseling and informed consent......Page 33
Current applications of genetic testing......Page 34
Molecular analyses: current approaches, new innovations, future directions......Page 39
Pharmocogenomics......Page 40
References......Page 41
PART II: A. Primary Genetic Diseases of Nephron Function......Page 44
Kidney function: a systems approach......Page 45
Walk through the nephron......Page 47
Integration of Anatomy and Physiology: Regulation......Page 66
Conclusion......Page 76
References......Page 77
Part II: B. Primary Genetic Diseases of the Glomerulus......Page 80
Renal glomerulus......Page 81
Glomerular basement membrane......Page 82
Alports disease......Page 85
Thin basement membrane nephropathy......Page 90
References......Page 95
Introduction......Page 101
Genetic defects of structural proteins......Page 102
Genetic defects of transcription factors......Page 108
SMARCAL1 and Schimke immuno-osseous dysplasia......Page 109
Galloway-Mowat syndrome......Page 110
References......Page 111
The podocyte......Page 116
Recessive FSGS: NPHS2......Page 118
Dominant FSGS......Page 120
Mitochondrial patterns of inheritance......Page 122
Animal models......Page 123
Secondary FSGS......Page 124
Approach to therapy......Page 125
References......Page 126
Part II: C. Primary Genetic Diseases of the Proximal Renal Tubules......Page 131
Physiology of renal glucose transport......Page 132
Inherited disorders of renal glucose transport......Page 134
References......Page 139
Primary inherited aminoacidurias......Page 142
Defects associated with heteromeric amino acid transporters......Page 143
Hartnup disorder......Page 151
The molecular bases of intestinal absorption and renal reabsorption of amino acids......Page 153
Basics of urate handling in human kidney......Page 161
Hereditary renal hypouricemia......Page 165
References......Page 168
History of the Fanconi syndrome......Page 171
Etiology......Page 172
Genetic causes......Page 173
Brief overview of proximal tubule transport......Page 175
Clinical pathophysiology......Page 176
Cellular mechanisms of proximal tubule transport defects......Page 181
Animal models of Fanconi syndrome......Page 186
Treatment......Page 188
References......Page 189
Cellular and molecular mechanisms of acidbase transport in the proximal tubule......Page 198
Definition and clinical features of proximal RTA......Page 202
Specific disorders causing proximal renal tubular acidosis......Page 205
References......Page 208
Physiology of CLC chloride channels......Page 212
Genetics......Page 217
Clinical phenotype and pathophysiology of dents disease......Page 218
Treatment......Page 221
References......Page 222
Part II: D. Primary Genetic Diseases of the Thick Ascending Limb of Henle......Page 226
History of Bartters and Gitelmans syndromes......Page 227
Mutations in NCC cause Gitelmans syndrome......Page 229
Uniformity of electrolyte phenotypes of patients with Gitelmans syndrome......Page 230
Pathophysiology of Gitelmans syndrome......Page 231
Gitelmans syndrome patients have reduced blood pressure and increased dietary salt intake......Page 232
Mutations in NKCC2......Page 233
Mutations in CLCNKB......Page 234
Combined mutations in CLCNKA and CLCNKB cause Bartters syndrome with sensorineural deafness......Page 235
Pathophysiology of Bartters syndrome......Page 236
Genotypephenotype correlations (Table 13.1) and diagnosis......Page 237
Treatment of patients with Gitelmans and Bartters syndromes......Page 239
Effects of the heterozygous state for Gitelmans and Bartters syndromes on blood pressure in the population......Page 240
References......Page 241
Physiology of magnesium homeostasis......Page 246
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC)......Page 248
Hypomagnesemia with secondary hypocalcemia (HSH)......Page 251
Autosomal dominant hypomagnesemia due to mutation in FXYD2......Page 253
Conclusions and future directions......Page 254
References......Page 255
Introduction......Page 259
The calcium-sensing receptor......Page 260
Role of the CaR in the kidney......Page 261
Familial hypocalciuric hypercalcemia (FHH) [OMIM 14598]......Page 262
Neonatal severe primary hyperparathyroidism (NSHPT) [OMIM 239200]......Page 266
Autosomal dominant hypoparathyroidism (ADH) (OMIM) [#601298]......Page 268
CaR-based therapeutics......Page 269
References......Page 270
Part II: E. Primary Genetic Diseases of the Distal Convoluted Tubule and Collecting Duct......Page 275
Pseudoaldosteronism......Page 276
ENaC and Na+ absorption in the ASDN......Page 277
Genotype–phenotype relationship......Page 278
Pathophysiology......Page 279
Mutations of the PY motif: a dual effect on ENaC function......Page 280
Mouse models of liddle's syndrome......Page 281
Pathogenesis......Page 282
References......Page 283
Clinical features of the syndrome of apparent mineralocorticoid excess (AME)......Page 285
Molecular studies of 11β-hydroxysteroid dehydrogenase (11-HSD)......Page 287
The HSD11B2 gene......Page 288
Molecular genetic analysis of apparent mineralocorticoid excess......Page 289
References......Page 292
Aldosterone biology......Page 295
Pseudohypoaldosteronism type 1......Page 296
Hypertension exacerbated by pregnancy......Page 299
The S810L mutation alters receptor specificity via a new intramolecular contact......Page 302
A splicing defect in MRL810 carriers......Page 303
References......Page 304
The role of the kidney in the regulation of blood pressure and electrolyte homeostasis......Page 307
Pseudohypoaldosteronism type II: a human model to explore coordinated regulation of blood pressure and electrolyte homeostasis......Page 308
Hypotheses of PHAII pathophysiology......Page 309
Molecular genetics of pseudohypoaldosteronism type II: evidence for genetic heterogeneity and discovery of the WNK protein kinases......Page 310
WNK1 and WNK4 localize to the aldosterone-sensitive distal nephron and extrarenal chloride-transporting extrarenal epithelia......Page 312
WNK1 and WNK4 regulate diverse aldosterone-sensitive mediators of ion transport via distinct mechanisms......Page 313
Pathophysiological mechanisms of PHAII......Page 316
Possible role of WNK1 and WNK4 in essential hypertension and WNKs as potential targets of novel therapeutics......Page 317
The role of the WNK kinases in the regulation of cell volume and intracellular chloride homeostasis......Page 318
WNK3: a brain-enriched kinase with reciprocal actions on the NKCCs and KCCs......Page 319
Conclusions and future directions......Page 320
References......Page 321
Definition and clinical features......Page 324
-intercalated cell function......Page 325
Autosomal dominant Distal renal tubular acidosis......Page 326
Autosomal recessive type 1 RTA......Page 328
Genotypephenotype correlations in primary distal RTA......Page 329
References......Page 330
Cellular actions of vasopressin......Page 333
Rareness and diversity of AVPR2 mutations......Page 334
Most mutant V2 receptors are not transported to the cell membrane and are retained in the intracellular compartments......Page 336
Nonpeptide vasoressin receptor antagonists act as pharmacological chaperones to functionally rescue misfolded mutant V2 receptors responsible for X-linked NDI......Page 337
References......Page 339
Aquaporin 2......Page 342
History of NDI......Page 345
The AQP2 gene......Page 346
Treatment for NDI......Page 349
Part III: Genetic Abnormalities of Renal Development and Morphogenesis......Page 354
Introduction......Page 355
Anatomic description of kidney development......Page 356
Specification of the nephric (Wolffian) duct and nephrogenic cord......Page 357
Metanephric kidney development......Page 359
References......Page 376
Diagnosis and clinical features......Page 383
Genetics of polycystic kidney disease......Page 388
Polycystin-1......Page 392
Polycystin-2......Page 393
Polyductin/fibrocystin......Page 394
Cilia......Page 395
Polycystic kidney diseases and cellular pathways......Page 397
Therapy in PKD......Page 403
Epidemiology......Page 415
Clinical features of NPHP......Page 416
Pathology......Page 418
Molecular genetics of NPHP: An etiological classification of NPHP......Page 423
Function of nephrocystins and pathogenesis of NPHP......Page 425
Diagnostics: Molecular genetics, imaging, and laboratory studies......Page 429
Therapy, prognosis, and genetic counseling......Page 430
Introduction......Page 437
History......Page 438
Epidemiology......Page 440
Genetics......Page 441
Pathophysiology......Page 443
Clinical manifestations......Page 444
Diagnosis......Page 446
Treatment......Page 447
References......Page 449
Renal developmental defects......Page 452
Kidney development......Page 454
Human syndromes associated with renal dysgenesis......Page 457
Acknowledgments......Page 475
Part IV: Inherited Neoplastic Diseases Affecting the Kidney......Page 483
Von hippel-lindau disease......Page 484
Other manifestations......Page 486
Management of patients with VHL......Page 487
Hereditary papillary renal cell cancer......Page 488
Birt-hogg-dub syndrome......Page 490
Hereditary leiomyomatosis and renal cell carcinoma......Page 491
References......Page 493
Wilms tumor: Histology, genetics, and associated syndromes......Page 496
The WT1 gene, mRNAs, and proteins......Page 499
The role of WT1 (–KTS) vs. WT1(+KTS) isoforms......Page 501
WT1 function during kidney development......Page 503
Conclusions......Page 506
References......Page 507
Clinical features of TSC......Page 513
Clinical and molecular genetics of TSC......Page 516
Genotype-phenotype correlations......Page 519
Molecular pathogenesis of tuberous sclerosis......Page 521
Therapies for TSC......Page 525
References......Page 526
Part V: Systemic Diseases with Renal Involvement: Monogenic Disorders......Page 529
Clinical features and natural history......Page 530
Establishing the diagnosis......Page 532
LMX1B: gene structure, mutations in NPS and their predicted effect......Page 533
History of the LMX1B gene and animal models of NPS and Lmx1b function......Page 536
Role of Lmx1b during kidney development......Page 537
Pathogenesis of NPS and important questions......Page 538
References......Page 539
Mitochondrial genome and genetics......Page 543
Focal segmental glomerulosclerosis (FSGS)......Page 544
Interstitial nephritis......Page 545
Fanconis syndrome......Page 546
Electrolyte abnormalities......Page 547
Hypertension......Page 548
Treatment......Page 549
References......Page 550
Introduction......Page 554
Biochemistry......Page 556
Genetics......Page 558
Diagnosis/screening......Page 561
Treatment/management......Page 564
Unclassified hyperoxaluria......Page 565
References......Page 566
Genetics......Page 570
Function of OCRL1 gene product (ocrl1)......Page 571
Neurologic manifestations......Page 572
Renal manifestations......Page 573
Carrier detection......Page 574
Treatment......Page 576
References......Page 577
The classic phenotype......Page 580
Heterozygotes for the classic phenotype......Page 584
The later-onset variants......Page 585
Pathology......Page 586
The metabolic and molecular defects in fabry disease......Page 587
Diagnosis......Page 588
Treatment......Page 589
Enzyme replacement therapy......Page 590
Future therapies......Page 593
References......Page 595
History......Page 600
Clinical features and presentation (Table 36.1)......Page 602
Perils of fructose poisoning in the clinical environment......Page 604
Effects of hereditary fructose intolerance on the kidney......Page 605
Pathological injury in hereditary fructose intolerance......Page 608
Metabolism of fructose......Page 609
Primary biochemical defect in fructose intolerance......Page 610
The enzymatic defect......Page 611
The environmental factor: fructose, a ubiquitous nutrient......Page 612
Molecular pathology of aldolase B deficiency......Page 613
Diagnosis of hereditary fructose intolerance......Page 615
Treatment and prognosis......Page 618
Prevention of fructose intolerance by genetic screening......Page 619
References......Page 620
The BOR phenotype......Page 625
The genetics of BOR syndrome......Page 627
References......Page 629
Introduction......Page 632
Purine metabolism......Page 634
Single gene disorder for overproduction type hyperuricemia......Page 635
Single gene disorder for decreased excretion type hyperuricemia......Page 637
References......Page 639
Clinical course......Page 642
Diagnosis and treatment......Page 643
Causative gene and encoded protein......Page 644
Function of cystinosin......Page 646
CTNS mutations......Page 647
Cystinosin-deficient mouse model......Page 656
References......Page 658
Introduction......Page 661
HTI: a severe liver and kidney disease......Page 662
Molecular genetics of HTI......Page 663
Site-specific reversion of mutations in HTI and restoration of enzyme activity......Page 664
Animal models of HTI......Page 665
Gene and cellular therapy as potential treatments in HTI......Page 666
References......Page 668
Clinical presentation......Page 672
The G6Pase complex and pathophysiology of GSD-I......Page 674
The molecular basis of GSD-Ib......Page 675
Kidney disease associated with GSD-I......Page 677
Renal disease in GSD-I and diabetes mellitus......Page 681
Treatment of GSD-I......Page 682
References......Page 684
Molecular pathophysiology of Wilson disease......Page 688
Renal copper excretion and transport......Page 689
Renal tubular injury and other findings......Page 690
Drug-induced renal injury......Page 691
References......Page 692
General aspects of renal phosphate handling......Page 693
A molecular view of renal phosphate transport......Page 695
Primary inherited defects in renal phosphate handing......Page 700
Defects in renal phosphate handling secondary to extrarenal inherited defects......Page 701
Conclusion and outlook......Page 705
Acknowledgments......Page 706
References......Page 707
Part VI: Systemic Hereditary Diseases with Renal Involvement: Multifactorial Diseases......Page 713
Clinical overview of lupus nephritis......Page 714
Genetic predisposition to SLE......Page 716
Pathogenesis of lupus nephritis......Page 718
Nephritic susceptibility loci mapped in murine lupus models......Page 719
References......Page 722
Definition and clinical features......Page 726
Pathogenesis......Page 727
Genetic epidemiology......Page 731
Molecular genetics......Page 736
Conclusions......Page 740
Overview......Page 747
Animal models of diabetic nephropathy......Page 748
Familial factors in diabetic nephropathy......Page 749
Candidate pathways of diabetic nephropathy......Page 750
The search for genetic factors in type 1 diabetic nephropathy......Page 755
The search for type 2 diabetic nephropathy genes......Page 756
Clinical presentation and epidemiology......Page 768
Pathogenesis......Page 771
Treatment......Page 781
Conclusion......Page 785
References......Page 786