Human Hemoglobin Genetics

by G.R. Honig, J.G. Adams

Overview

The discovery in the late 1940's that sickle cell anemia is a "molecular disease" of hemoglobin was the crucial advance that gave birth to the scientific discipline of human molecular genetics. In subsequent years, with the continued expansion of knowledge about the biology and genetics of the hemoglobins, and particularly as a result of the characterization of the very large numbers of globin gene mutations, the human hemoglobin system has remained as the premier model of gene expression at the molecular level in man. With the recent explosion of new information about the genetic properties of the hemoglobins, it appears inevitable that this gene system will continue to occupy a unique position in human molecular genetics for many years in the future. Hemoglobin genetics has also recently come of age as a diagnostic and clinical discipline. The heightening of public awareness in recent years about sickle cell disease, thalassemia, and other inherited disorders has brought increasing demands for carrier detection services as well as for genetic counseling and education. The more recent development of prac­ tical and reliable methods for the antenatal diagnosis of hemoglobin dis­ orders has further increased the scope of clinical hemoglobin genetics, and it can be anticipated that these potent diagnostic techniques will have increasing application in the years ahead.

Product Details

ISBN-13:	9783709188002
Publisher:	Springer Vienna
Publication date:	02/12/2012
Edition description:	1986
Pages:	452
Product dimensions:	6.69(w) x 9.61(h) x 0.04(d)

Table of Contents

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 of the 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.