The Molecular Basis of Mutant Hemoglobin Dysfunction

The Molecular Basis of Mutant Hemoglobin Dysfunction contains the proceedings of the Comprehensive Sickle Cell Center Symposium on the Molecular Basis of Mutant Hemoglobin Dysfunction held at the University of Chicago, Chicago, Illinois, USA, on 7-10 October 1979. The symposium aims to document the progress of research efforts and bring together biochemists, geneticists, clinicians, counselors, and administrators, so that ensuing research will bring science to bear more effectively on these diseases. The volume contains 31 chapters organized into six sections. Section I presents two papers on the influence of fetal hemoglobin on the risk of complications and ocular manifestations of sickle cell disease. The papers in Section II deal with normal and abnormal gene expression. Section IIII is devoted to the structural analysis of mutant hemoglobins and their aggregates. Section IV focuses on evaluations of the physical and molecular basis of mutant hemoglobin dysfunction. The presentations in Section V cover cell biology and pathophysiology of sickle cell disease. Section VI reviews the status of the therapy of sickle cell disease.

Dedication Preface Plenary Address: Molecular Disease Section I: Some Clinical Problems Stated for the Molecular Biologist The Influence of Fetal Hemoglobin on the Risk of Complications of Sickle Cell Anemia Ocular Manifestations of Sickle Cell Disease Section II: Expression of Normal and Abnormal Genes Introductory Remarks Organization of Normal and Abnormal Human Globin Genes by Restriction Enzyme Analysis The a-Globin Genotype as a Determinant of Hematologic Parameters in Sickle Cell Trait Characterization of Linked Human Globin Genes by Molecular Cloning Procedures Regulation of Human Globin Gene Expression after Gene Transfer The Introduction of Normal and Mutant Globin Genes into Mammalian Cells Using SV40 Vectors Section III: Structure Analysis of Mutant Hemoglobins and their Aggregates Introductory Remarks Flexibility of the NH2-Terminal Region of the ß Chains of Hemoglobin: Correlation with the Gelation Properties of Deoxyhemoglobin S Contacts Between Molecular Surfaces in Crystals of Deoxygenated Human Hemoglobins A, C, F, and S Double Filaments: the Basic Structural Unit of Deoxygenated Sickle Hemoglobin Fibers A Plausible Molecular Model for the 14-Filament Fibers of Sickle Cell Hemoglobin Polymorphic Assemblies of Double Strands of Sickle Cell Hemoglobin and their Role in Fiber and Crystal Formation The Effect of Additive Conformation on Enhancement of Deoxyhemoglobin Polymerization Section IV: Molecular Dynamics of Dysfunction and Aggregation Introductory Remarks Subunit Assembly and Interactions in Normal and Abnormal Human Hemoglobins Is It Possible to Deduce the Interaction Between Two Proteins from Their Three-Dimensional Structure? Peptide Inhibitors of the Gelation of Sickle Hemoglobin Oxygen Binding and the Gelation of Sickle Cell Hemoglobin Rheological Properties of the Gelled Phase of Hemoglobin S Decreased Binding of 2,3-Diphosphoglycerate to Deoxy Hemoglobin S: A Polymerization-Independent Functional Abnormality Section V: Cell Biology and Pathophysiology of Sickle Cell Disease Introductory Remarks Red Cell Membrane Alterations Associated with the Sickling Phenomenon Sickle Erythrocyte Adherence to Cultured Human Endothelial Cells Section VI: Prospects for Therapy at the Molecular Level Introductory Remarks Prospects for Therapy at the Molecular Level: Historical Review Covalent Inhibitors of Sickling Weak Binding Gases as Modulators of Hemoglobin Function Chemical Modifications of Hemoglobin S at the 2,3-Diphosphoglycerate Binding Site: An Approach to Therapy of Sickle Cell Disease Index