Advances in Human Genetics 11

ISBN-13: 9781461583059 / Angielski / Miękka / 2013 / 385 str.

Spis treści

1 The Pi Polymorphism: Genetic, Biochemical, and Clinical Aspects of Human ?1-Antitrypsin.- Historical Review.- Pi Variants.- Nomenclature of Genetic Variants.- Techniques for Identification.- Characterization of Pi Variants.- Population Studies of the Pi Alleles.- Linkage and Mapping for the Pi Locus.- Selective Mechanisms.- Biochemical Aspects.- Microheterogeneity.- Antigenicity.- Inhibition of Proteases.- ?1-Antitrypsin and the Clotting System.- ?1-Antitrypsin and the Immune Response.- Biochemical Characterization of Genetic Variants of ?1-Antitrypsin.- Metabolism of ?1-Antitrypsin.- Synthesis and Distribution.- Concentration of ?1-Antitrypsin in Plasma.- Association between Pi Types and Disease.- Pulmonary Disease.- Liver Disease.- Primary Liver Carcinoma.- Other Malignancies.- Kidney Disease.- Rheumatoid Arthritis.- Miscellaneous Diseases.- Chromosome Aberrations.- Protease Inhibitor Systems and Disease Mechanisms.- Interrelated Systems.- Leukocyte Proteases and ?1AT.- Unresolved Problems.- References.- 2 Segregation Analysis.- Mathematical Formulation of Genetic Models.- Joint Genotypic Distribution of Mating Individuals.- Relationship between Phenotype and Genotype.- Mode of Inheritance.- Sampling Scheme.- The Likelihood Method.- Likelihood of Randomly Sampled Data.- Likelihood When Sampling via Selected Probands.- Parameter Estimation and Testing Hypotheses.- Examples of Segregation Analysis.- Segregation of Dopamine-?-hydroxylase (DBH) Activity in Selected Families.- Segregation of Hypercholesterolemia in a Large Pedigree.- Segregation of Phenylthiocarbamide (PTC) Taste Sensitivity.- Segregation of Immunoglobulin E (IgE) Levels.- Conclusion.- Appendix: Notes on Computational Methods.- References.- 3 Genetic, Metabolic, and Biochemical Aspects of the Porphyrias.- Tetrapyrroles.- Structure of Porphyrins.- Physicochemical Properties of Porphyrins.- Enzymes and Intermediates of the Heme Biosynthetic Pathway.- Formation of ?-Aminolevulinic Acid (ALA).- Formation of Porphobilinogen (PBG).- Formation of Uroporphyrinogen (UROgen).- Formation of Coproporphyrinogen (COPROgen).- Formation of Protoporphyrinogen (PROTOgen).- Formation of Protoporphyrin IX (PROTO IX).- Formation of Heme.- Regulation of Enzymes of Heme Biosynthesis.- Liver.- Erythroid Cells.- Other Cell Types.- Classification of the Human Porphyrias.- Congenital Erythropoietic Porphyria (CEP).- Erythropoietic Protoporphyria (EPP).- Acute Intermittent Porphyria (AIP).- Hereditary Coproporphyria (HCP).- Variegate Porphyria (VP).- Porphyria Cutanea Tarda (PCT).- Acute Hepatic Porphyria Resulting from ALA Dehydratase Deficiency.- Porphyria in Association with Other Disorders.- Hereditary Porphyrias in Animals.- References.- 4 The Molecular Genetics of Thalassemia.- The New Genetics.- Globin Gene Organization in the Cellular DNA.- The Organization and Structure of Human Globin Genes.- Globin Gene Expression and mRNA Biogenesis.- The Nature of Thalassemias.- ?-Thalassemias.- ?-Thalassemias.- Thalassemias Associated with Structurally Abnormal Globins.- DNA Polymorphisms in the ?-like Globin Gene Cluster.- Prenatal Diagnosis of Hemoglobin Disorders by DNA Analysis.- Additional Approaches to the Correlation of Gene Structure and Function.- Summary and Conclusions.- References.- 5 Advances in the Treatment of Inherited Metabolic Diseases.- Metabolic Manipulation.- Dietary Restriction.- Substrate Depletion Techniques.- Surgical Bypass Procedures.- Metabolic Inhibition.- Product Replacement.- Gene Product Therapy.- Cofactor Supplementation.- Enzyme Induction/Feedback Repression.- Allotransplantation.- Enzyme Replacement Therapy.- Rationale.- Early Trials of Enzyme Replacement.- Requisites for Enzyme Replacement Therapy.- Human and Animal Trials—Replacement with Purified Enzymes.- Human Trials with Purified Homologous Enzymes.- Animal Model Trials—In Vivo Fate of Purified Enzymes.- Therapeutic Considerations.- Enzyme Delivery Strategies.- Carrier Mediated Delivery.- Clinical Application of Enzyme Delivery Strategies.- Prospects for Enzyme Replacement.- Gene Therapy.- Production of Human Gene Products.- Gene Transfer.- References.- Addenda.