Human Heredity 11th Edition by Michael Cummings

Exercise 9

The First Molecular Disease
Linus Pauling, a two-time Nobel Prize winner, once recalled that when he first heard a description of how red blood cells change shape in sickle cell anemia, he had the idea that sickle cell anemia is really a molecular disease. He thought the disorder must involve an abnormality of the hemoglobin molecule caused by a mutated gene.
Early in 1949, Pauling and his student Harvey Itano began a series of experiments to determine whether there is a difference between normal hemoglobin and sickle cell hemoglobin.
They obtained blood samples from people with sickle cell anemia and from unaffected individuals. They extracted hemoglobin from the blood samples, placed it in a tube with an electrode at each end, and passed an electrical current through the tube. Hemoglobin from individuals with sickle cell anemia migrated toward the cathode, indicating that it had a positive electrical charge. Samples of normal hemoglobin migrated in the opposite direction (toward the anode), indicating that this hemoglobin had a net negative electrical charge. In the same year, James Neel, working with patients with sickle cell in the Detroit area, demonstrated that sickle cell anemia is a genetic trait, inherited as an autosomal recessive condition.
Pauling and his colleagues published a paper on their results and incorporated Neel's findings into their discussion. They concluded that a mutant gene involved in the synthesis of hemoglobin causes sickle cell anemia. The idea that a genetic disorder can be caused by a defect in a single molecule was revolutionary. Pauling's idea about a molecular disease helped reignite interest in human biochemical genetics and played a key role in our understanding of the molecular nature of mutations.
After Watson and Crick worked out the structure of DNA, Crick was eager to show that mutant genes produce mutant proteins whose amino acid sequences differ from those of the normal protein. He persuaded Vernon Ingram to look for such differences. Because of Pauling's work, Ingram settled on hemoglobin as the protein he would analyze. He cut hemoglobin into pieces with the enzyme trypsin and separated the 30 resulting fragments. He noticed that normal hemoglobin and sickle cell hemoglobin differed in only one fragment-a peptide about 10 amino acids long. Ingram then worked out the amino acid sequence of that fragment in normal and sickle cell hemoglobin. In 1956, he reported that there is a difference of only one amino acid (glutamic acid in normal hemoglobin and valine in sickle cell hemoglobin) between the two proteins. This finding confirmed that there is a relationship between a mutant gene and a mutant gene product and established a way of thinking about mutations and disease that changed human genetics.
Although sickle cell anemia is inherited as a recessive trait, are there conditions where a heterozygous carrier might show sickle cell formation?