PNH and the GPI-Linked Proteins
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Table of contents
- Cover
- Copyright Pageiv
- Contentsv
- Contributorsxi
- Prefacexiii
- Chapter 1. A Brief History of PNH1
- The Diagnosis of PNH8
- Summary15
- References16
- Chapter 2. Genetics of PNH21
- Biochemical Genetics of PNH in Somatic Cells21
- The PIG-A Gene23
- The PIG-A Protein24
- Detecting Mutations in the PIG-A Gene27
- Germ Line PIG-A Mutations32
- The Spectrum of Somatic Mutations in the PIG-A Gene33
- PIG-A Mutations without PNH40
- Structure–Function Relationships41
- Correlation between Phenotypes and Genotypes42
- Comparison of the Spectrum of Mutations in Three X-Linked Genes: PIG-A, FVIII, and G6PD42
- Conclusion43
- References44
- Chapter 3. Hemolysis in PNH49
- Introduction49
- The Classical Pathway of Complement55
- The Alternative Pathway of Complement61
- Phenotypic Mosaicism64
- Functional Basis of the Abnormal Sensitivity of the Erythrocytes of PNH to Complement-Mediated Lysis68
- Treatment of Hemolysis83
- Summary and Conclusions86
- References89
- Chapter 4. Thrombotic Complications in PNH101
- Introduction101
- Incidence of Thrombosis in PNH102
- Factors Associated with Venous Thrombosis103
- Platelet Abnormalities in PNH104
- Role of Red Cell and Platelet Microvesicles107
- Urokinase Activator Receptor (uPAR) and Cell-Mediated Fibrinolysis108
- Treatment of Thrombosis in PNH109
- Summary109
- References110
- Chapter 5. Bone Marrow Failure in PNH113
- Introduction113
- Pathophysiology of Marrow Failure in PNH115
- An Immune Model of PNH Pathogenesis120
- Clinical Course and Treatment of Marrow Failure in PNH127
- Summary130
- References131
- Chapter 6. Animal Models of PNH139
- Introduction139
- Mouse Piga Gene141
- In Vitro Differentiation of PIGA(– ) ES Cells143
- Chimeric Mice Bearing PIGA(– ) Hematopoietic Stem Cells149
- Hematopoiesis by Cells from Patients with PNH in SCID Mice154
- Conclusions and Perspectives155
- References155
- Chapter 7. The Function of GPI-Anchored Proteins159
- Introduction159
- GPI-Linked Proteins and Cell Signaling161
- Role of GPI-Anchored Proteins in Insulin Action166
- GPI-Anchored Proteins Function as Receptors166
- GPI Anchors and Membrane Structure168
- Summary170
- References171
- Chapter 8. GPI in Lower Animals179
- Introduction179
- Structures of Protozoal GPIs180
- Evidence for GPI-Mediated Signaling in Mammalian Cell Biology182
- Signal Transduction in Host Cells by Protozoal GPIs185
- Parasite GPIs as Functional Toxins and Pathogenicity Factors187
- Regulation of Macrophage Function by Glycoconjugates of Leishmania188
- Regulation of Host Cells by Ceramide-Containing GPIs of T. cruzi189
- Insulin-Mimetic Activities of Protozoal GPIs189
- CD1d-Restricted NK T Cells and Immunity to GPI-Anchored Proteins190
- Conclusions191
- References192
- Chapter 9. Synthesis of the GPI Anchor199
- Introduction199
- GPI Biosynthetic Pathway200
- Mammalian and Yeast GPI-Anchor Defective Mutants203
- GPI-Anchor Addition to Proteins207
- Biological Implications of GPI Anchoring210
- Conclusions213
- References214
- Chapter 10. Functional and Structural Organization of GPI-Anchored Proteins in Cellular Membranes221
- Introduction221
- GPI-Anchor Function and the ‘‘Raft’’ Hypothesis221
- Lateral Heterogeneity in Cell Membranes222
- Detergent-Resistant Membranes and Their Connection with Rafts223
- Evidence for Rafts in Living Cell Membranes227
- Involvement of Rafts in Biosynthetic and Endocytic Sorting230
- Rafts and Signaling by GPIAPs232
- In Conclusion233
- References233
- Chapter 11. Structure and Function of GPI-Specific Phospholipases239
- Introduction: GPI Anchors and Phospholipases239
- Biochemical Properties of Plasma GPI-PLD245
- Distribution of GPI-PLD in Tissues and Cells252
- Physiological Role of GPI-PLD257
- References262
- Appendix: Sequence of the Coding Region of the Human PIG-A Gene269
- Index271
Paroxysmal Nocturnal Hemoglobinuria (PNH) has been recognized for over a century. This mysterious disease is now understood at the level of the gene and the protein. The pathophysiology is related to a class of cell surface proteins with distinctive biochemical and physical characteristics. Recently it has been acknowledged that PNH is not rare, and once sensitive assays--based on the chemistry of the proteins--can be applied to many patients.
Written by international experts in the field, this book includes a number of distinctive characteristics, such as the clinical features of PNH, the mechanism of hemolysis, the biochemistry of glycosylphosphoinositol anchors, and the chemistry and biophysics of GPI-anchored proteins.
This unique and timely volume will have a wide audience, including hematologists and oncologists with a clinical interest in this disease, as well as basic biochemists, immunologists, and cell biologists studying this class of proteins.
Key Features
* Outlines the chemical features of PNH
* Explains the mechanism of hemolysis
* Includes work on the biochemistry of glycophosphoinositol anchors
* Contains descriptions of the chemistry and biophysics of GPI-anchored proteins
Written by international experts in the field, this book includes a number of distinctive characteristics, such as the clinical features of PNH, the mechanism of hemolysis, the biochemistry of glycosylphosphoinositol anchors, and the chemistry and biophysics of GPI-anchored proteins.
This unique and timely volume will have a wide audience, including hematologists and oncologists with a clinical interest in this disease, as well as basic biochemists, immunologists, and cell biologists studying this class of proteins.
Key Features
* Outlines the chemical features of PNH
* Explains the mechanism of hemolysis
* Includes work on the biochemistry of glycophosphoinositol anchors
* Contains descriptions of the chemistry and biophysics of GPI-anchored proteins