Molecular genetics of inherited eye disorders

Front Matter......Page 1
CONTENTS......Page 5
PREFACE TO THE SERIES......Page 7
PREFACE......Page 9
HEREDITY......Page 10
CONTRIBUTORS......Page 11
1. BACKGROUND TO MOLECULAR GENETIC PRINCIPLES AND TECHNIQUES......Page 15
I a ANATOMY OF THE GENOME......Page 16
I b ANATOMY OF THE GENE......Page 20
II GENETIC MAPPING......Page 24
The mouse genetic map......Page 28
Transgenics and ES cell technology......Page 29
III THE TOOLS OF THE MOLECULAR GENETICIST......Page 31
1 Separation of nucleic acids on the basis of size and structure......Page 32
3. Production of pure nucleic acids - synthesis, cloning......Page 33
4. Nucleic acid visualisation and quantification......Page 35
5. Specific sequences of DNA can be identified by hybridisation......Page 38
REFERENCES......Page 42
I INTRODUCTION......Page 43
II STRUCTURE OF THE Drosophila COMPOUND EYE AND METHODS OF MONITORING RETINAL DEGENERATION......Page 44
1 Mutants of the Rhodopsin Gene, ninaE......Page 47
2 Mutants of the Phospholipase C Gene, norpA......Page 51
3 Mutants of the trp Gene......Page 54
4 Mutants of the rdgB Gene......Page 56
5 Mutants of the ninaC Gene......Page 58
IV DISCUSSION......Page 59
V ACKNOWLEDGMENTS......Page 61
VI REFERENCES......Page 62
INTRODUCTION......Page 67
Genetic studies......Page 68
Functional studies......Page 69
Molecular genetic studies......Page 72
Functional consequences of mutations in adRP genes......Page 73
Choroideremia......Page 75
Abetalipoproteinaemia......Page 77
Vitelliform macular dystrophy Best’s disease......Page 78
Adult vitelliform macular dystrophy......Page 79
Bietti’s crystalline dystrophy......Page 80
Fundus flavimaculatus......Page 81
Bull’s eye dystrophies including cone and cone-rod dystrophies......Page 82
Sorsby\'s fundus dystrophy pseudoinflammatory macular dystrophy......Page 83
Colour vision defects......Page 84
Congenital stationary night blindness......Page 85
Oguchi\'s disease......Page 87
Fundus albipunctatus......Page 88
CONCLUSION......Page 89
REFERENCES......Page 90
INTRODUCTION......Page 103
Biochemical Process......Page 104
TRP1......Page 106
Nystagmus......Page 107
Retinal Pigment and Foveal Development......Page 108
Overview......Page 109
Clinical phenotype......Page 110
Molecular phenotype......Page 112
Mouse Tyrosinase Mutations......Page 116
Overview......Page 117
Clinical phenotype......Page 118
Molecular Phenotype......Page 120
Unclassified Types......Page 121
Hermansky-Pudlak Syndrome......Page 122
Mouse Models for Platelet Storage Pool Deficiencies......Page 123
X-Linked Recessive OA OA1......Page 124
Autosomal Recessive Ocular Albinism OA2......Page 125
Diagnosis of Albinism......Page 126
REFERENCES......Page 127
5. INHERITED RETINAL DEGENERATIONS IN THE MOUSE......Page 137
Biochemical and Molecular Biological Studies......Page 138
Isolation of a Candidate cDNA for the rd Gene......Page 144
Characterization of the Candidate cDNA for the rd Gene......Page 145
Molecular Genetic Studies......Page 146
Identification of the Product of the Candidate rd Gene......Page 147
Conclusive Demonstration that the β Subunit of Cyclic GMP-Phosphodiesterase is the Site of the rd Mutation......Page 148
Identification of the Defective rds Gene......Page 150
The Human Counterpart of the Mouse rds Gene Causes Human Retinitis Pigmentosa and Macular Degenerations......Page 152
MAPPING OF OTHER GENES EXPRESSED IN RETINAL TISSUES......Page 153
Molecular Genetic Studies in the Mouse Could Increase our Understanding of Human Diseases......Page 158
REFERENCES......Page 159
INTRODUCTION......Page 166
MUTATIONS OF THE RHODOPSIN GENE IN ADRP......Page 171
TRANSGENIC MICE WITH THE ADRP PRO-23-HIS MUTATION......Page 177
A DIVERSE MOLECULAR PATHOLOGY IN ADRP......Page 178
REFERENCES......Page 182
DEFINITION OF AMD......Page 186
HETEROGENEITY OF AMD......Page 187
HERITABILITY OF AMD......Page 192
MOLECULAR APPROACHES TO DISEASE GENE IDENTIFICATION......Page 194
CONCLUSION......Page 203
REFERENCES......Page 204
RETINOBLASTOMA GENETICS......Page 209
FINDING THE RB GENE......Page 211
CYTOGENETIC ANALYSIS OF RB TUMOURS......Page 212
ISOLATION OF THE RBI GENE......Page 214
MUTATIONS IN RB TUMOURS......Page 215
THE FUNCTION OF THE RBI GENE......Page 216
RBI MUTATIONS IN OTHER TUMOURS......Page 218
CLINICAL APPLICATIONS OF RBI ISOLATION......Page 219
RISK ASSESSMENT......Page 220
IDENTIFICATION OF CAUSATIVE MUTATIONS......Page 222
REFERENCES......Page 224
SUMMARY......Page 228
INTRODUCTION......Page 229
1 Monochromacy......Page 230
2 Dichromacy......Page 231
3 Trichromacy......Page 232
Variation in normal color vision and in normal pigments......Page 234
PIONEERING STUDIES OF THE MOLECULAR GENETICS OF COLOR VISION......Page 236
MUTATIONAL PATHWAYS: FROM NORMAL TO DEFECTIVE GENOTYPES......Page 240
A new concept of normal genes makes abnormal gene arrangements easily explainable......Page 245
Results from Southern analysis re-examined......Page 246
Defective genes......Page 252
SPECTRAL TUNING AND NORMAL COLOR VISION VARIATIONS......Page 255
No anomalous pigments in color anomaly......Page 260
SUMMARY ? A THEORY OF THE CONES, CONE PIGMENTS AND CONE PIGMENT GENES OF HUMAN COLOR VISION......Page 263
REFERENCES......Page 265
INTRODUCTION......Page 269
X-LINKED RP......Page 270
GENETIC MAPPING OF XLRP GENES......Page 272
RP3......Page 274
RP2......Page 276
PROBLEMS CAUSED BY HETEROGENEITY......Page 278
WHAT ARE THE RELATIVE PROPORTIONS OF THE RP3 AND RP2-TYPE OF XLRP?......Page 279
RP2, XL-CSNB AND MYOPIA......Page 280
REFERENCES......Page 282
INTRODUCTION......Page 287
CLASSIFICATION OF INHERITED STATIONARY NYCTALOPIA BASED ON FUNDUS APPEARANCE......Page 288
CLINICAL MANIFESTATIONS......Page 289
Basics of Electroretinography......Page 291
Electroretinography and CSNB......Page 293
Electrophysiology of the X-Linked Carrier......Page 297
SPECIAL CONSIDERATIONS WITH ÅIED AND DMD......Page 298
Basics of Dark Adaptation......Page 300
CLINICAL EVOLUTION OF CSNB......Page 301
PATHOGENESIS......Page 302
MAPPING OF THE GENES FOR CSNB......Page 303
REFERENCES......Page 305
CLINICAL ASPECTS......Page 312
Contiguous Gene Deletion Syndromes......Page 313
Chromosomal Abnormalities Associated with Classical CHM......Page 314
1. Chromosomal walking and jumping......Page 315
Cloning of CHM cDNAs......Page 316
Cloning of Part of the CHM Structural Gene......Page 318
Expression Pattern of the CHM Gene......Page 319
SSCP Analysis......Page 321
CLONING OF THE MURINE HOMOLOGUE AND A HUMAN AUTOSOMAL HOMOLOGUE FROM CHROMOSOME 1......Page 323
THE CHM PROTEIN MAY BE A COMPONENT OF A GERANYLGERANYL TRANSFERASE......Page 324
REFERENCES......Page 325
Ophthalmological findings......Page 329
Systemic signs......Page 331
Differential diagnosis......Page 332
Penetrance and Incidence......Page 333
Cytogenetics......Page 334
Regional assignment of DNA probes to the proximal Xp......Page 335
Deletion studies......Page 336
Long range restriction mapping......Page 337
The structure of the NDP gene......Page 338
Mutation analysis and diagnostic implications......Page 340
The function of the predicted protein......Page 341
REFERENCES......Page 342
EPIDEMIOLOGY......Page 347
PREVALENCE......Page 348
Anatomical features......Page 349
Visual acuity and refraction......Page 352
Electro-oculography, electroretinography, dark adaptation, fluorescein angiography......Page 353
Therapy......Page 354
Phenotypes of heterozygotes......Page 355
Linkage studies in retinoschisis......Page 356
Diagnostic procedures......Page 358
SUMMARY AND CONCLUSIONS......Page 360
REFERENCES......Page 361
Usher Syndrome Phenotypes......Page 366
HEARING LOSS IN USHER SYNDROME......Page 367
VESTIBULAR DEFICIT......Page 370
Visual Phenotype......Page 373
Inter- and Intrafamilial Variability......Page 374
Mental Retardation and /or Other CNS Dysfunction.......Page 375
Pattern Of Inheritance......Page 376
Localization of Usher Type I to Chromosome 14q......Page 377
Linkage of Usher type I to chromosome 11......Page 379
Linkage of the Usher Type II Gene to 1q......Page 382
Discovery of USH2 Heterogeneity......Page 384
CONCLUSIONS......Page 385
REFERENCES......Page 386
Musculoskeletal Manifestations......Page 389
Ocular manifestations......Page 391
INHERITANCE......Page 392
Brief overview......Page 393
The Fibrillin gene and its product......Page 394
Marfan Syndrome and mutations in the Fibrillin gene......Page 397
ANIMAL MODEL......Page 398
CLINICAL MANAGEMENT......Page 399
FUTURE DIRECTIONS......Page 400
REFERENCES......Page 401
Incidence and Inheritance......Page 405
Ocular Findings......Page 406
Neuromuscular signs......Page 408
Skeletal signs......Page 409
Ophthalmic pathology......Page 410
Central nervous system pathology......Page 411
BIOCHEMICAL FINDINGS......Page 412
Positional Cloning......Page 413
REFERENCES......Page 414
INTRODUCTION......Page 419
α-Crystallins......Page 421
Expression pattern......Page 422
β-Crystallins......Page 423
Genomic organization......Page 424
γ-Crystallins......Page 427
Genomic organization......Page 428
Evolution of the γ-crystallin genes......Page 429
CATARACTS......Page 430
Human Inherited Cataracts......Page 431
Genetic factors......Page 432
Linkage studies......Page 433
Chromosomal abnormalities associated with congenital cataracts......Page 434
ANIMAL MODELS......Page 435
Mutation in the βB2-crystallin......Page 436
The Elo Mouse......Page 437
13/N Guinea Pig......Page 438
Mutagen-Induced Cataract Mice......Page 439
CONCLUSION......Page 440
REFERENCES......Page 441
Phenotype......Page 450
The Aniridia Locus Maps to 11p13......Page 452
Characterization of the 11p13 WAGR Region......Page 453
Cloning of candidate aniridia genes......Page 455
Small eye : a mouse model for aniridia......Page 457
Mouse mutations......Page 458
Human mutations......Page 460
Immediate Clinical Applications......Page 462
A role for PAX6 mutations in other eye disorders?......Page 463
Identifying the affected tissue......Page 464
PAX6 affects formation of the lens......Page 465
What controls PAX6 and what are its targets?......Page 466
REFERENCES......Page 467
MITOCHONDRIAL DNA AND OXPHOS......Page 473
THE UNIQUE GENETICS OF MTDNA......Page 476
MtDNA MUTATIONS AND OPHTHALMIC DISEASE......Page 477
Leber\'s Hereditary Optic Neuropathy LHON......Page 478
Moderate-risk LHON mutations......Page 481
Low-risk LHON mutations......Page 483
Neurogenic Muscle Weakness, Ataxia, and Retinitis Pigmentosa NARP......Page 484
MtDNA Rearrangements and the Eye......Page 485
MtDNA Deletions......Page 486
REFERENCES......Page 490
GLOSSARY......Page 495
INDEX......Page 518