The Genetic Basis of Male Infertility

ISBN-13: 9783642085543 / Angielski / Miękka / 2010 / 306 str.

Ken McElreavey

Opis

Every year there are new and exciting developments in assisted human reproduction, but how much do we really know about the underlying causes of infertility? This volume explores recent progress in the understanding of the genetics of spermatogenesis and male infertility. Topics include fundamental advances and current problems in the development and function of the testis, an outline of clinical findings in male infertility and an overview of the role of the Y chromosome in male fertility. Comprehensive critiques of posttranscriptional control during spermatogenesis, mammalian meiotic sterility, and comparative genetics of human spermatogenesis from the perspective of yeast, Drosophila and mice provide a global overview of the field.

Spis treści

Clinical Aspects of Male Infertility.- 1 Introduction.- 1.1 Definition of Couple and Male Infertility.- 1.2 Assisted Reproduction and Clinical Andrology.- 2 The Elements of Standard Medical Workup.- 2.1 Medical and Familial History.- 2.2 Physical Examination.- 2.3 Diagnostic Tests.- 3 Aetiology of Male Infertility.- 3.1 Infertility Due to Antispermatogenic Agents.- 3.2 Infertility Due to Endocrine Disorders (Hypogonadotrophic Hypogonadism).- 3.3 Infertility Due to Impairment of Sperm Transport and/or Accessory Gland Infections.- 3.4 Autoimmune Infertility.- 3.5 Infertility and Varicocele.- 3.6 Infertility Due to Coital Disorders.- 3.7 Infertility and Cryptorchidism.- 4 Infertility Due to Genetic Disorders.- 4.1 Chromosomal Abnormalities.- 4.2 Klinefelter Syndrome.- 4.3 Other Chromosomal Abnormalities.- 4.4 Male Infertility from Defect in Meiosis.- 5 Monogenic Diseases.- 5.1 The Kartagener Syndrome or Immotile Cilia Syndrome.- 5.2 Androgen Insensitivity Syndromes.- 5.3 The Infertile Male Syndrome.- 5.4 X-Linked Spinal and Bulbar Muscular Atrophy (Kennedy Disease).- 5.5 Persistent Mullerian Duct Syndrome.- 5.6 Inactivating FSH Receptor Mutation.- 6 Clinical Considerations of Genetic Abnormalities.- 7 Treatment of the Infertile Male.- References.- The Cell Biology and Molecular Genetics of Testis Determination.- 1 Introduction.- 2 Human Sex Determination is Chromosomally Based.- 2.1 Sex Reversal.- 3 Gonadal Sex Differentiation.- 3.1 Testicular and Ovarian Morphogenesis in Human Embryos.- 3.2 The Importance of the Supporting Cell Lineage.- 3.3 The Contribution of the Mesonephros.- 3.4 Genes Involved in Formation of the Gonadal Primordium.- 4 The Testis-Determining Factor (TDF).- 4.1 SRY is TDF.- 4.2 The SRY Protein and Its Targets.- 4.3 Is SRY a Negative Regulator?.- 5 The SOX9 Gene and Testis Determination.- 5.1 Campomelic Dysplasia, Sex Reversal and SOX9.- 5.2 Embryonic Expression of Sox9.- 5.3 Where is SOX9 Placed in the Testis-determining Cascade?.- 6 Orphan Nuclear Receptors and Sex Determination.- 6.1 Steroidogenic Factor 1 (SF1).- 6.2 DAX1 and Gonadal Differentiation.- 7 Summary: A Genetic Cascade for Testis Determination.- References.- The Sertoli Cell-Germ Cell Interactions and the Seminiferous Tubule Interleukin-1 and Interleukin-6 System.- 1 Organisation of the Testis.- 1.1 Spermatogenesis.- 1.2 The Sertoli Cell.- 1.3 The Interstitial Tissue.- 2 Endocrine Regulation of Testicular Function.- 3 Paracrine Regulation of Testicular Function.- 3.1 The Place of the IL-1/IL-6 System in the Sertoli Cell-Germ Cell Communication Network.- 3.1.1 IL-1 and IL-6.- 3.2 Sertoli Cell-Germ Cell Interactions.- 3.2.1 The Role of the Sertoli Cell.- 3.2.2 The Action of Germ Cells.- 3.3 Sources of Seminiferous-Tubule IL-1 and IL-6.- 3.3.1 Tubular IL-1.- 3.3.2 Sertoli Cell IL-6.- 3.4 Testicular IL-1 and IL-6 Receptors.- 3.5 Testicular Effects of IL-1 and IL-6.- 3.6 The Regulation of Sertoli Cell IL-1 and IL-6 by Germ Cells and the Synchronisation of the Seminiferous Epithelium Cycle.- 3.6.1 Residual Bodies and Production of Sertoli Cell IL-1 and IL-6.- 3.6.2 Control of Sertoli Cell IL-1 and IL-6 Production by Germ Cell Cytokines.- 4 Conclusion.- References.- Leydig Cell Function and Its Regulation.- 1 Introduction.- 2 Leydig Cell Morphology and Endocrine Function.- 2.1 Morphology of the Leydig Cell.- 2.2 The Hypothalamo-Pituitary-Leydig Cell Axis.- 2.2.1 Hypothalamo-Pituitary Activity and Androgen Secretion.- 2.2.2 The Role of the Testicular Vasculature.- 2.2.3 Androgen Metabolism, Action and Negative Feedback Regulation.- 2.3 Leydig Cell Steroidogenesis.- 2.4 Non-Steroidal Products of the Leydig Cell.- 3 Leydig Cell Development.- 3.1 Species Variation in Leydig Cell Development.- 3.2 Fetal, Perinatal and Prepubertal Development of the Leydig Cell in the Human.- 3.3 Pubertal Development of the Leydig Cell.- 3.4 The Ethane Dimethane Sulfonate Recovery Model.- 3.5 Hormonal Regulation of Adult Leydig Cell Development.- 3.6 Local Factors and Leydig Cell Development.- 4 Molecular Regulation of the Leydig Cell.- 4.1 Luteinizing Hormone and the LH Receptor.- 4.2 Intracellular Signalling Events and cAMP.- 4.3 Cholesterol Mobilization.- 4.3.1 Cholesterol Transport Proteins.- 4.3.2 Steroidogenic Acute Regulatory Protein.- 4.3.3 The Role of the Cytoskeleton.- 4.4 Regulation of the Steroidogenic Enzymes.- 4.4.1 Chronic Regulation of the Steroidogenic Machinery.- 4.4.2 Transcriptional Regulation of Steroidogenesis.- 4.5 Other Transducing Mechanisms.- 4.5.1 Calcium.- 4.5.2 Chloride.- 4.5.3 Protein Kinase C.- 4.5.4 Arachidonic Acid and Its Metabolites.- 5 Extrinsic Regulation of the Leydig Cell by Factors Other than LH.- 5.1 Anterior Pituitary Hormones: FSH, Prolactin, and Growth Hormone.- 5.2 Regulation by the Seminiferous Tubules.- 5.3 Cytokines and Growth Factors.- 5.4 Autocrine Regulation.- 5.4.1 Androgen-Mediated Autoregulation.- 5.4.2 Leydig Cell Desensitization.- 5.5 Glucocorticoids.- 5.6 Neuropeptides.- 5.7 Other Factors.- 6 Leydig Cell Function and Infertility.- References.- Post-Transcriptional Control and Male Infertility.- 1 Introduction.- 2 The Need for Translational Control.- 3 Regulatory Elements in Untranslated Sequences.- 4 The Protamine mRNA Is Stored in a Ribonucleoprotein Particle.- 5 Sequence-Specific RNA Binding Proteins.- 6 Premature Translation of Prm1 mRNA.- 7 Activation of Translationally Repressed mRNAs.- 8 Orphan RNA Binding Proteins.- 9 Perspectives.- References.- An Integration of Old and New Perspectives of Mammalian Meiotic Sterility.- 1 Introduction.- 1.1 The Meiotic Cell Division.- 1.2 Meiotic-Specific Structures.- 1.3 Identified Protein Components of Meiotic-Specific Structures.- 1.3.1 Components of the Synaptonemal Complex.- 1.3.2 Meiotic Nodules.- 2 Sterility from a “Process-Oriented” Perspective.- 2.1 Errors in Synapsis.- 2.1.1 The Asynaptic Phenotype and Sterility.- 2.1.2 Theoretical Links Between Asynapsis and Sterility.- 2.1.2.3 Mismatch Repair and Mammalian Meiotic Sterility.- 2.2 Errors in the Meiotic Divisions (Metaphase I Through Anaphase II).- 3 Sterility from the Perspective of Cell Cycle Checkpoint Control.- 4 Summary and Conclusions.- References.- Mutations of the Cystic Fibrosis Gene and Congenital Absence of the Vas Deferens.- 1 Introduction.- 2 CF and CBAVD: A Common Genetic Background.- 2.1 Mutation Analysis Results and the 5T-Tract Variant.- 3 Pathogenesis of CBAVD.- 4 Spermatogenesis and Epididymal Length.- 5 Remaining Questions.- 6 Conclusions.- References.- Mitochondrial Function and Male Infertility.- 1 Introduction.- 2 Mitochondrial Diseases.- 3 Mitochondrial Function and Aging.- 4 Mitochondrial Biogenesis During Spermatogenesis.- 5 Mitochondrial Organization in the Spermatozoon.- 6 Regulation of Oxidative Phosphorylation in Mitochondria.- 7 Abnormal Mitochondria and Infertility.- 8 Mitochondrial Respiratory Chain, mtDNA and Infertility.- 9 Reactive Oxygen Species Generation and Human Spermatozoa.- 10 ATP Concentration, Creatine Kinase Activity and Infertility.- 11 Mitochondrial Inheritance.- 12 Conclusion.- References.- The Human Y Chromosome and Male Infertility.- 1 Structure of the Human Y Chromosome.- 1.1 Pseudoautosomal Regions.- 1.2 Non-Recombining Region.- 2 Functions Associated with the Non-Recombining Region of the Human Y chromosome.- 2.1 Sex Determination.- 2.2 Turner Syndrome.- 2.3 Histocompatibility Y Antigen (H–Y).- 2.4 Gonadoblastoma.- 2.5 Male Infertility.- 3 Yq-Specific Genes and Gene Families.- 4 Function of Y-Specific Genes in Spermatogenesis.- 4.1 RBMY.- 4.2 DAZ.- 5 Which Genes Underlie the AZF Phenotypes?.- 6 Frequency of Yq Micro deletions.- 7 Microdeletions and Genotype/Phenotype Relationships.- 8 Mechanism of Y Chromosome Microdeletions.- 9 Y Chromosome Susceptibility Haplotypes.- 10 Perspectives.- References.- Spermatogenesis and the Mouse Y Chromosome: Specialisation Out of Decay.- 1 The Unique Y Chromosome.- 2 The Functions of the Mouse Y Chromosome.- 2.1 Somatic Functions of the Mouse Y Chromosome.- 2.2 Germ Cell Functions.- 3 The Molecular Genetics of the Mouse Y Chromosome.- 3.1 Overview.- 3.2 The Long Arm.- 3.2.1 Molecular Structure.- 3.2.2 Deletion of the Long Arm.- 3.3 The Pericentric Region.- 3.3.1 Molecular Structure.- 3.3.2 Deletion of the Pericentric Region.- 3.3.3 Deletion of the Long Arm and the Pericentric Region.- 3.4 The Short Arm.- 3.4.1 Molecular Structure.- 3.4.2 Deletion of the Short Arm.- 3.4.3 Genes in the Sxrb Deletion Interval.- 3.5 The Mouse Y Chromosome in Spermatogenesis — Conclusions.- 4 Comparison of the Mouse and Human Y Chromosome Maps.- 4.1 Distinct Gene Organisation.- 4.2 A Block of Syntenic Homology.- 4.3 Implications for Spermatogenesis.- 5 Evolution of the Y Chromosome.- 5.1 Sex Chromosome Evolution Theory.- 5.1.1 The Origin of the Non-Recombining Y Chromosome (NRY).- 5.1.2 The Decay of Genes on the Non-Recombining Y Chromosome (NRY).- 5.1.3 Accumulation of Male-Enhancing Mutations.- 5.2 Evolution of Y Genes and Spermatogenesis.- 5.2.1 X–Y Homologous Genes.- 5.2.1.1 The Ubiquitin Activating Enzyme.- 5.2.1.2 Dosage Compensation.- 5.2.1.3 Restriction of Expression to the Germ Line.- 5.2.2 Y-Autosomal Genes.- 5.2.2.1 DAZ.- 5.2.2.2 RBMY.- 5.2.3 Genes of Unknown Origin.- 5.2.3.1 TSPY.- 5.2.3.2 Ssty.- 5.2.4 Y Chromosome Gene Evolution and Function.- 6 General Conclusions.- 7 The Future.- References.- The Comparative Genetics of Human Spermatogenesis: Clues from Flies and Other Model Organisms.- 1 Introduction.- 2 Model Organisms for Studying the Genetic Causes of Subfertility in Man.- 2.1 Mendelian Genetics and Male Subfertility.- 2.2 Spermatogenesis: An Ancient, Conserved Process of Cellular and Subcellular Differentiation.- 2.3 Model Organisms.- 2.3.1 Yeast.- 2.3.2 Chlamydomonas.- 2.3.3 Caenorhabditis elegans.- 2.3.4 Mouse.- 2.3.5 Zebra Fish.- 2.3.6 Drosophila.- 2.3.6.1 In Flies, the Y Chromosome Carries Only a Few Genes Essential for Spermatogenesis.- 2.3.6.2 Hundreds of Genes on the X Chromosome and Autosomes Are Involved in Spermatogenesis of Drosophila.- 2.3.6.3 Phenotypic Analysis of Sterile Male Flies Suggests That Most of These Genes Are Expressed in the Male Germ Cells.- 2.2.6.4 Sperm Components Differentiate by Independent Programs in Drosophila.- 2.3.6.5 Genetic Switches Operating During Male Germ Cell Development in Drosophila.- 2.3.6.6 Many Male Sterile Mutations in Flies Are Pleiotropic.- 3 The Comparative Genetics of Male Germ Cell Differentiation in Flies and Man.- 3.1 How Many Male Fertility Genes Exist in Man?.- 3.2 Why Does Such a Large Fraction of All Genes Participate in Spermatogenesis?.- 4 Population Studies and Mutations Affecting Male Fertility in Flies and Man.- 5 Concluding Remarks.- References.