Human Hemoglobin Genetics

1. Introduction.- A. The Hemoglobins in Human Biology and Genetics - An Overview.- B. Historical Foundations of Human Hemoglobin Genetics.- 1. Early Genetic Studies of Sickle Cell Anemia and Thalassemia.- 2. Abnormal Hemoglobins as Molecular Diseases.- 3. The Genetic Basis of the Thalassemias.- 4. Discoveries of Additional Globin Genes and Linkage Relationships.- 5. Methodological Advances in Hemoglobin Research.- 2. The Human Hemoglobins.- A. Hemoglobin Structure and Function.- 1. The Structure of the Hemoglobin Molecule and Its Subunits.- 2. Hemoglobin Function and Its Control.- B. The Normal Human Hemoglobins and Their Globin Subunits.- 1. The Globin Polypeptide Chains.- 2. The Normal Human Hemoglobins.- 3. The Hemoglobins in Gestation and Development.- 3. The Human Globin Genes.- A. DNA Structure and Function.- B. Recent Methodologie Advances in the Study of Genes and Their Structure.- C. Globin Gene Localization and Organization.- 1. The Chromosomal Location of the Globin Genes.- 2. The Linear Arrangement of the Globin Genes in the Chromosomes.- a) The ?-Gene Cluster.- b) The ?-Gene Cluster.- D. The Structure of the Globin Genes.- 1. Globin Gene Organization: Coding and Intervening Sequences.- 2. Flanking Regions of the Globin Genes and Their Role in Gene Transcription.- 3. The DNA Sequences ofthe Globin Genes.- a) The ?-Gene Family.- b) The ?-Gene Family.- E. The Evolution of the Globin Genes.- 4. Hemoglobin Synthesis and Globin Gene Expression.- A. Hemoglobin Synthesis and Its Regulation.- 1. Transcription of the Globin Genes.- a) The Composition and Structure of Nuclear Chromatin.- b) Properties of Transcriptionally Active Chromatin.- c) Chromosomal Proteins and Gene Transcription.- d) Regulation of Gene Transcription.- e) Synthesis of the Primary Gene Transcript.- f) Processing of the mRNA Precursor.- i) The Splicing Reaction.- ii) The 5?-terminal Cap.- iii) Polyadenylation of the mRNA Precursor.- g) Structure and Properties of the Human Globin mRNA's.- 2. Globin Translation and Its Regulation.- a) Translation Initiation.- b) Polypeptide Chain Elongation and Termination.- c) Heme Synthesis and Its Regulation.- d) Regulation of Globin Chain Translation and the Role of Heme.- e) Coordination of the Synthesis of the ?- and non-?-Globin Chains.- B. Regulation of the Expression of the Normal Globin Genes.- 1. The ?-Globin Gene Group.- 2. Expression of the ?- and ?-Globin Genes.- 3. Gene Switching and Its Regulation.- a) Globin Gene Switching in Embryonic and Fetal Development.- b) ?-Globin Gene Expression in the Older Child and Adult.- c) Elevated Levels of Hb F in Post-Infancy Development.- d) Genetic Factors in Hb F Expression.- 5. The Globin Gene Mutations - A. Mechanisms and Classification.- A. Mechanisms of Globin Gene Mutation.- 1. Single Base Changes ("Point Mutations").- 2. Genetic Recombination.- 3. Nucleotide Deletions and Insertions.- B. Classification of the Globin Gene Mutations.- 1. Mutations Associated with Globin Structural Abnormalities.- a) Single Point Mutations which Produce Amino Acid Substitutions.- b) Double Point Mutations.- c) Point Mutations Causing Premature Translation Termination.- d) Point Mutations Producing Extended Globin Chains.- e) Deletion and Insertion Mutants.- f) Frame Shift Mutants.- g) Fusion-Gene Mutants.- h) Complex Globin Gene Mutations.- 2. The Thalassemia Mutations.- a) Gene-Deletion Thalassemia Mutations.- i) ?-Globin Gene Deletions.- ii) ?-Globin Gene Deletions in Association with ? Chain Structural Mutants.- iii) Deletions Involving the ?-Globin Gene Complex.- b) The "Non-Deletion" Thalassemia Mutations.- i) Mutations Affecting Globin Gene Transcription.- ii) Base Substitution Involving the Translation Initiation Codon.- iii) Mutations Producing Premature Termination Codons.- iv) Splice Junction Mutations.- v) Mutations Producing Abnormal Splicing Sites.- vi) Polyadenylation/Transcription-Termination Signal Mutations.- 3. Hereditary Persistence of Fetal Hemoglobin (HPFH) Mutations.- 4. Globin Gene Somatic Mutations.- 6. The Globin Gene Mutations - B. Their Phenotypes and Clinical Expression.- A. Sickle Cell Disease.- 1. Pathogenesis.- 2. Hematological and Clinical Features.- 3. The Sickle Cell Disease Syndromes.- 4. Heterozygous Hb S (Sickle Cell Trait).- 5. Hb F and Sickle Hemoglobin Expression.- 6. Other Genetic Abnormalities that Affect the Expression of Sickle Cell Disease.- B. Intracellular Hemoglobin Crystallization: Hb C.- C. Erythrocytosis: Abnormal Hemoglobins with Increased Oxygen Affinity.- D. Congenital Cyanosis.- 1. Abnormal Hemoglobins with Low Oxygen Affinity.- 2. The Hb M Variants.- E. Hemolytic Anemia ("Congenital Heinz-Body Anemia"): The Unstable Hemoglobins.- F. The Thalassemias.- 1. Pathogenesis.- 2. The Phenotypes of the Thalassemia Syndromes.- a) The ?-Thalassemia Syndromes.- b) Structural Hemoglobin Variants with ?-Thalassemia-like Expression.- c) The ? Thalassemia Syndromes.- d) Structural Hemoglobin Variants that are Expressed as ? Thalassemia.- e) ? Thalassemia/? Thalassemia Syndromes.- f) The ? Thalassemias.- g) Thalassemia/ Abnormal Hemoglobin Syndromes.- G. The Syndromes of Hereditary Persistence of Fetal Hemoglobin.- 1. The Phenotypes of the HPFH Syndromes.- 2. Hereditary Persistence of Fetal Hemoglobin in Combination with Thalassemia or Structural Hemoglobin Variants.- 3. Chromosomal Abnormalities Associated with a Prolongation or Delay of Hemoglobin Switching.- H. Precocious Synthesis of Adult Hemoglobin.- 7. The Genetics of the Human Globin Gene Loci: Formal Genetics and Gene Linkage.- A. The Formal Genetics of the Human Hemoglobin System.- 1. The ?-Globin Locus.- 2. The ?-Globin Locus.- 3. The ?-Globin Loci.- 4. The ?-Globin Locus.- 5. The ?-Globin Loci.- 6. The ?-Globin Locus.- B. New Globin-Gene Mutations.- C. Aequired (Non-genetic) Thalassemias.- D. Linkage Relationships Involving Polymorphic Sites in the Regions of the Globin Genes.- 1. Restriction Fragment Length Polymorphisms (RFLPs) in the ?-Globin Gene Cluster.- 2. Linkage Relationships of ?-Globin Gene Restriction Fragment Length Polymorphisms.- 3. Polymorphisms Within the ?-Globin Gene.- 4. Haplotype Associations with ? Thalassemia.- 8. The Geographic Distribution of Globin Gene Variation.- A. Distribution of the Hemoglobin Variants and Thalassemias.- B. The Malaria Hypothesis.- 1. Geographic and Epidemiologic Evidence in Support of the Malaria Hypothesis.- 2. Experimental Evidence Related to Malarial Parasite Infectivity.- C. Molecular Approaches to the Study of Genetic Diversity of the Globin Gene Alleles.- 1. Origins of the ?E-Globin Gene.- 2. The Origins of the ?S-Globin Gene.- 3. Other Globin Mutations Associated with Multiple Haplotypes.- 9. Laboratory Identification, Screening, Education, and Counseling for Abnormal Hemoglobins and Thalassemias.- A. The Laboratory Identifieation of Abnormal Hemoglobins and Thalassemias.- 1. Blood Count Measurements.- 2. Electrophoretic Methods.- a) Hemoglobin Electrophoresis at Alkaline pH.- b) Citrate Agar Gel Electrophoresis.- c) Globin Chain Electrophoresis.- d) Measurement of the Electrophoretic Mobility of Hemoglobins and Globin Chains.- e) Isoelectric Focusing.- 3. Other Methods for Abnormal Hemoglobin Characterization.- a) Tests for Sickle Hemoglobin.- b) Testing for Hemoglobin Functional Abnormalities and Instability.- 4. The Quantitative Estimation of Hemoglobins.- 5. Structural Characterization of Abnormal Hemoglobins.- B. Screening for Abnormal Hemoglobins and Thalassemias.- 1. Screening to Determine the Variety and Frequency of Abnormal Globin Genes.- 2. Newborn Screening.- 3. Screening for Abnormal Hemoglobins Prior to Surgery or Childbirth.- 4. Screening of Volunteer Adults.- a) Approaches to Education and Screening.- b) Genetic Counseling.- C. Antenatal Diagnosis.- 1. Diagnostic Methods Utilizing Fetal Blood.- a) Fetal Blood Sampling.- b) Analysis of Fetal Blood.- 2. Methods Which Utilize Fetal DNA.- a) Fetal DNA Sampling.- b) Fetal DNA Analysis.- 3. The Impact of Programs for Antenatal Diagnosis.- 10. Approaches to the Treatment of the Hemoglobin Disorders.- A. Current Forms of Treatment for Patients with Hemoglobin Disorders.- 1. Transfusion Therapy.- 2. Other Therapy for the Management of Patients with Sickle Cell Disease and Thalassemia.- B. New Directions in Therapy.- 1. Anti-sickling Therapy.- 2. Bone Marrow Transplantation.- 3. Chemotherapy for the Stimulation of Fetal Hemoglobin Synthesis.- 4. Gene Therapy.- Table A-1. The ?-Globin Gene Mutations.- Table A-2. The ?-Globin Gene Mutations.- Table A-3. The ?-Globin Gene Mutations.- Table A-6. The Fusion Gene Mutations.- References.