ISBN: 3-540-66264-2
TITLE: The Genetic Basis of Male Infertility
AUTHOR: McElreavey, Ken (Ed.)
TOC:

Clinical Aspects of Male Infertility
Csilla Krausz and Gianni Forti
1 Introduction 1
1.1 Definition of Couple and Male Infertility 1
1.2 Assisted Reproduction and Clinical Andrology 3
2 The Elements of Standard Medical Workup 4
2.1 Medical and Familial History 4
2.2 Physical Examination 4
2.3 Diagnostic Tests 4
3 Aetiology of Male Infertility 6
3.1 Infertility Due to Antispermatogenic Agents 6
3.2 Infertility Due to Endocrine Disorders (Hypogonadotrophic Hypogonadism) 7
3.3 Infertility Due to Impairment of Sperm Transport and/or Accessory Gland Infections 7
3.4 Autoimmune Infertility 8
3.5 Infertility and Varicocele 9
3.6 Infertility Due to Coital Disorders 9
3.7 Infertility and Cryptorchidism 9
4 Infertility Due to Genetic Disorders 10
4.1 Chromosomal Abnormalities 10
4.2 Klinefelter Syndrome 11
4.3 Other Chromosomal Abnormalities 12
4.4 Male Infertility from Defect in Meiosis 12
5 Monogenic Diseases 12
5.1 The Kartagener Syndrome or Immotile Cilia Syndrome 12
5.2 Androgen Insensitivity Syndromes 13
5.3 The Infertile Male Syndrome 13
5.4 X-Linked Spinal and Bulbar Muscular Atrophy (Kennedy Disease) 14
5.5 Persistent Mullerian Duct Syndrome 14
5.6 Inactivating FSH Receptor Mutation 15
6 Clinical Considerations of Genetic Abnormalities 15
7 Treatment of the Infertile Male 16
References 17
The Cell Biology and Molecular Genetics of Testis Determination
Craig A. Smith and Andrew H. Sinclair
1 Introduction 23
2 Human Sex Determination is Chromosomally Based 24
2.1 Sex Reversal 24
3 Gonadal Sex Differentiation 25
3.1 Testicular and Ovarian Morphogenesis in Human Embryos 25
3.2 The Importance of the Supporting Cell Lineage 28
3.3 The Contribution of the Mesonephros 30
3.4 Genes Involved in Formation of the Gonadal Primordium 30
4 The Testis-Determining Factor (TDF) 31
4.1 SRY is TDF 32
4.2 The SRY Protein and Its Targets 33
4.3 Is SRY a Negative Regulator? 35
5 The SOX9 Gene and Testis Determination 36
5.1 Campomelic Dysplasia, Sex Reversal and SOX9 36
5.2 Embryonic Expression of Sox9 38
5.3 Where is SOX9 Placed in the Testis-determining Cascade? 39
6 Orphan Nuclear Receptors and Sex Determination 39
6.1 Steroidogenic Factor 1 (SF1) 39
6.2 DAX1 and Gonadal Differentiation 41
7 Summary: A Genetic Cascade for Testis Determination 44
References 46
The Sertoli Cell-Germ Cell Interactions and the Seminiferous Tubule Interleukin-1 and Interleukin-6 System
B. Jgou, J. P. Stphan, C. Cudicini, E. Gmez, F. Bauch, C. Piquet-Pellorce, and A. M. Touzalin
1 Organisation of the Testis 53
1.1 Spermatogenesis 53
1.2 The Sertoli Cell 54
1.3 The Interstitial Tissue 54
2 Endocrine Regulation of Testicular Function 55
3 Paracrine Regulation of Testicular Function 55
3.1 The Place of the IL-1/IL-6 System in the Sertoli Cell-Germ Cell Communication Network 56
3.1.1 IL-1 and IL-6 56
3.2 Sertoli Cell-Germ Cell Interactions 57
3.2.1 The Role of the Sertoli Cell 57
3.2.2 The Action of Germ Cells 58
3.3 Sources of Seminiferous-Tubule IL-1 and IL-6 59
3.3.1 Tubular IL-1 59
3.3.2 Sertoli Cell IL-6 60
3.4 Testicular IL-1 and IL-6 Receptors 60
3.5 Testicular Effects of IL-1 and IL-6 61
3.6 The Regulation of Sertoli Cell IL-1 and IL-6 by Germ Cells and the Synchronisation of the Seminiferous Epithelium Cycle 61
3.6.1 Residual Bodies and Production of Sertoli Cell IL-1 and IL-6 62
3.6.2 Control of Sertoli Cell IL-1 and IL-6 Production by Germ Cell Cytokines 63
4 Conclusion 63
References 64
Leydig Cell Function and Its Regulation
M. P. Hedger and D. M. de Kretser
1 Introduction 69
2 Leydig Cell Morphology and Endocrine Function 70
2.1 Morphology of the Leydig Cell 70
2.2 The Hypothalamo-Pituitary-Leydig Cell Axis 70
2.2.1 Hypothalamo-Pituitary Activity and Androgen Secretion 70
2.2.2 The Role of the Testicular Vasculature 72
2.2.3 Androgen Metabolism, Action and Negative Feedback Regulation 72
2.3 Leydig Cell Steroidogenesis 73
2.4 Non-Steroidal Products of the Leydig Cell 75
3 Leydig Cell Development 76
3.1 Species Variation in Leydig Cell Development 76
3.2 Fetal, Perinatal and Prepubertal Development of the Leydig Cell in the Human 76
3.3 Pubertal Development of the Leydig Cell 77
3.4 The Ethane Dimethane Sulfonate Recovery Model 79
3.5 Hormonal Regulation of Adult Leydig Cell Development 79
3.6 Local Factors and Leydig Cell Development 80
4 Molecular Regulation of the Leydig Cell 81
4.1 Luteinizing Hormone and the LH Receptor 81
4.2 Intracellular Signalling Events and cAMP 83
4.3 Cholesterol Mobilization 84
4.3.1 Cholesterol Transport Proteins 84
4.3.2 Steroidogenic Acute Regulatory Protein 84
4.3.3 The Role of the Cytoskeleton 85
4.4 Regulation of the Steroidogenic Enzymes 85
4.4.1 Chronic Regulation of the Steroidogenic Machinery 85
4.4.2 Transcriptional Regulation of Steroidogenesis 86
4.5 Other Transducing Mechanisms 86
4.5.1 Calcium 86
4.5.2 Chloride 87
4.5.3 Protein Kinase C 87
4.5.4 Arachidonic Acid and Its Metabolites 88
5 Extrinsic Regulation of the Leydig Cell by Factors Other than LH 88
5.1 Anterior Pituitary Hormones: FSH, Prolactin, and Growth Hormone 88
5.2 Regulation by the Seminiferous Tubules 89
5.3 Cytokines and Growth Factors 90
5.4 Autocrine Regulation 91
5.4.1 Androgen-Mediated Autoregulation 91
5.4.2 Leydig Cell Desensitization 91
5.5 Glucocorticoids 92
5.6 Neuropeptides 92
5.7 Other Factors 93
6 Leydig Cell Function and Infertility 93
References 94
Post-Transcriptional Control and Male Infertility
Robert E. Braun
1 Introduction 111
2 The Need for Translational Control 113
3 Regulatory Elements in Untranslated Sequences 114
4 The Protamine mRNA Is Stored in a Ribonucleoprotein Particle 117
5 Sequence-Specific RNA Binding Proteins 118
6 Premature Translation of Prm1 mRNA 120
7 Activation of Translationally Repressed mRNAs 121
8 Orphan RNA Binding Proteins 122
9 Perspectives 124
References 125
An Integration of Old and New Perspectives of Mammalian Meiotic Sterility
Terry Ashley
1 Introduction 131
1.1 The Meiotic Cell Division 132
1.2 Meiotic-Specific Structures 133
1.3 Identified Protein Components of Meiotic-Specific Structures 135
1.3.1 Components of the Synaptonemal Complex 136
1.3.2 Meiotic Nodules 138
2 Sterility from a "Process-Oriented" Perspective 144
2.1 Errors in Synapsis 144
2.1.1 The Asynaptic Phenotype and Sterility 144
2.1.2 Theoretical Links Between Asynapsis and Sterility 147
2.1.2.3 Mismatch Repair and Mammalian Meiotic Sterility 150
2.2 Errors in the Meiotic Divisions (Metaphase I Through Anaphase II) 153
3 Sterility from the Perspective of Cell Cycle Checkpoint Control 154
4 Summary and Conclusions 162
References 163
Mutations of the Cystic Fibrosis Gene and Congenital Absence of the Vas Deferens
Pasquale Patrizio and Debra G. B. Leonard
1 Introduction 175
2 CF and CBAVD: A Common Genetic Background 176
2.1 Mutation Analysis Results and the 5T-Tract Variant 179
3 Pathogenesis of CBAVD 180
4 Spermatogenesis and Epididymal Length 181
5 Remaining Questions 182
6 Conclusions 184
References 184
Mitochondrial Function and Male Infertility
Thomas Bourgeron
1 Introduction 187
2 Mitochondrial Diseases 188
3 Mitochondrial Function and Aging 191
4 Mitochondrial Biogenesis During Spermatogenesis 192
5 Mitochondrial Organization in the Spermatozoon 193
6 Regulation of Oxidative Phosphorylation in Mitochondria 195
7 Abnormal Mitochondria and Infertility 198
8 Mitochondrial Respiratory Chain, mtDNA and Infertility 199
9 Reactive Oxygen Species Generation and Human Spermatozoa 201
10 ATP Concentration, Creatine Kinase Activity and Infertility 203
11 Mitochondrial Inheritance 204
12 Conclusion 206
References 206
The Human Y Chromosome and Male Infertility
Ken McElreavey, Csilla Krausz, and Colin E. Bishop
1 Structure of the Human Y Chromosome 211
1.1 Pseudoautosomal Regions 211
1.2 Non-Recombining Region 212
2 Functions Associated with the Non-Recombining Region of the Human Y chromosome 214
2.1 Sex Determination 214
2.2 Turner Syndrome 214
2.3 Histocompatibility Y Antigen (H-Y) 215
2.4 Gonadoblastoma 215
2.5 Male Infertility 216
3 Yq-Specific Genes and Gene Families 217
4 Function of Y-Specific Genes in Spermatogenesis 219
4.1 RBMY 219
4.2 DAZ 220
5 Which Genes Underlie the AZF Phenotypes? 222
6 Frequency of Yq Microdeletions 222
7 Microdeletions and Genotype/Phenotype Relationships 223
8 Mechanism of Y Chromosome Microdeletions 225
9 Y Chromosome Susceptibility Haplotypes 226
10 Perspectives 228
References 228
Spermatogenesis and the Mouse Y Chromosome: Specialisation Out of Decay
Michael J. Mitchell
1 The Unique Y Chromosome 233
2 The Functions of the Mouse Y Chromosome 234
2.1 Somatic Functions of the Mouse Y Chromosome 234
2.2 Germ Cell Functions 235
3 The Molecular Genetics of the Mouse Y Chromosome 236
3.1 Overview 236
3.2 The Long Arm 237
3.2.1 Molecular Structure 237
3.2.2 Deletion of the Long Arm 238
3.3 The Pericentric Region 240
3.3.1 Molecular Structure 240
3.3.2 Deletion of the Pericentric Region 241
3.3.3 Deletion of the Long Arm and the Pericentric Region 241
3.4 The Short Arm 242
3.4.1 Molecular Structure 242
3.4.2 Deletion of the Short Arm 243
3.4.3 Genes in the Sxrb Deletion Interval 243
3.5 The Mouse Y Chromosome in Spermatogenesis  Conclusions 245
4 Comparison of the Mouse and Human Y Chromosome Maps 246
4.1 Distinct Gene Organisation 246
4.2 A Block of Syntenic Homology 248
4.3 Implications for Spermatogenesis 248
5 Evolution of the Y Chromosome 250
5.1 Sex Chromosome Evolution Theory 250
5.1.1 The Origin of the Non-Recombining Y Chromosome (NRY) 250
5.1.2 The Decay of Genes on the Non-Recombining Y Chromosome (NRY) 250
5.1.3 Accumulation of Male-Enhancing Mutations 251
5.2 Evolution of Y Genes and Spermatogenesis 252
5.2.1 X-Y Homologous Genes 253
5.2.1.1 The Ubiquitin Activating Enzyme 254
5.2.1.2 Dosage Compensation 254
5.2.1.3 Restriction of Expression to the Germ Line 255
5.2.2 Y-Autosomal Genes 257
5.2.2.1 DAZ 257
5.2.2.2 RBMY 258
5.2.3 Genes of Unknown Origin 259
5.2.3.1 TSPY 259
5.2.3.2 Ssty 259
5.2.4 Y Chromosome Gene Evolution and Function 260
6 General Conclusions 262
7 The Future 263
References 263
The Comparative Genetics of Human Spermatogenesis: Clues from Flies and Other Model Organisms
Ron Hochstenbach and Johannes H. P. Hackstein
1 Introduction 271
2 Model Organisms for Studying the Genetic Causes of Subfertility in Man 272
2.1 Mendelian Genetics and Male Subfertility 272
2.2 Spermatogenesis: An Ancient, Conserved Process of Cellular and Subcellular Differentiation 272
2.3 Model Organisms 275
2.3.1 Yeast 275
2.3.2 Chlamydomonas 276
2.3.3 Caenorhabditis elegans 277
2.3.4 Mouse 277
2.3.5 Zebra Fish 278
2.3.6 Drosophila 278
2.3.6.1 In Flies, the Y Chromosome Carries Only a Few Genes Essential for Spermatogenesis 279
2.3.6.2 Hundreds of Genes on the X Chromosome and Autosomes Are Involved in Spermatogenesis of Drosophila 280
2.3.6.3 Phenotypic Analysis of Sterile Male Flies Suggests That Most of These Genes Are Expressed in the Male Germ Cells 281
2.2.6.4 Sperm Components Differentiate by Independent Programs in Drosophila 283
2.3.6.5 Genetic Switches Operating During Male Germ Cell Development in Drosophila 284
2.3.6.6 Many Male Sterile Mutations in Flies Are Pleiotropic 285
3 The Comparative Genetics of Male Germ Cell Differentiation in Flies and Man 285
3.1 How Many Male Fertility Genes Exist in Man? 286
3.2 Why Does Such a Large Fraction of All Genes Participate in Spermatogenesis? 288
4 Population Studies and Mutations Affecting Male Fertility in Flies and Man 290
5 Concluding Remarks 291
References 292
Subject Index 299
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