Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management

摘要

Few textbooks are devoted to a single molecule. Yet hemoglobin is a spectacular molecule, without which life would not be possible. The history of hemoglobin dates to 1840, when Friedrich Hunefeld and others discovered that hemoglobin carries oxygen. Approximately 100 years later, Max Perutz discovered the molecular structure of hemoglobin by x-ray crystallography and was awarded the Nobel Prize for this work. The entire genomic structure of hemoglobin is now known, allowing for vast new amounts of information about its role in health and disease. There are hundreds of different hemoglobins; some are specific for embryonic, fetal, and adult life, and others are variants. Some variants, such as hemoglobin S, have conferred protection for whole populations against malaria and other infectious diseases by trapping parasites within their membranes, allowing the parasites to be cleared in the re-ticuloendothelial system. Two prototypical abnormalities of hemoglobin account for most diseases: qualitative defects in heme (ie, sickle cell disease and its variants) and quantitative defects in the globin chain (ie, thalassemia). These latter abnormalities have become much better understood and amenable to study since the cloning and sequencing of human globin genes. More than a thousand globin chain variants have now been discovered, allowing for characterization of disease, elucidation of gene effects on protein encoding, and precise prenatal and postnatal diagnosis.