Linus Pauling introduced the concept of molecular disease by demonstrating that the gene for sickle cell anemia was directly related to a chemical alteration of hemoglobin in the red blood cells of affected individuals. A few years later, Vernon Ingram identified a single amino acid replacement at position 6 of the beta chains of sickle cell hemoglobin (HbS) and showed that the sequence of the remaining 145 amino acids of the beta chains and all 141 amino acids in the alpha chains of hemoglobin were unchanged compared to normal hemoglobin (HbA). Subsequently, others determined the exact nucleotide substitution mutation in the beta globin gene possessed by sickle cell patients.

These discoveries prompted a stampede of sorts to discover other hemoglobin variants and the corresponding mutations in DNA. There are now on the order of 1000 different mutations known to affect the amino acid sequence or production of hemoglobin. While most of these are single-base-substitution mutations, deletions and insertions are known. The consequences vary from benign to severe, as in the case of thalassemias. Many medical biochemists have made a career studying these usually rare hemoglobinopathies.

Using a list of hemoglobinopathies (alpha-chain, beta-chain, thalassemias), pick an interesting example to investigate as the basis for a 3+ page, double-spaced, well-organized report that has the following elements:

• A description of the mutation and its consequences for hemoglobin structure, function, and stability. (Append a photocopy of the title page of the original article describing the mutation and/or variant hemoglobin.)
• If appropriate, include a photocopy of the three-dimensional structure of hemoglobin showing the location or region of the molecule affected.
• Describe any clinical and/or functional effects of the mutation.
• Provide citations to all references and illustrations (if not original) using the standard citation format of the Journal of Biological Chemistry. Part of the purpose of this assignment is for you to demonstrate your ability to find, use, and properly document information from the library.

This assignment will be evaluated for its composition, content, clarity of presentation, and depth of your analysis. Remember, this should be your synthesis of the information, not a paraphrasing of the words of others. Late papers will not be accepted.

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Last updated: 25 April 1999 by Hal White

Copyright 1999, Department of Chemistry and Biochemistry, University of Delaware