General Description Of The Hemoglobinopathies

Disorders of the globin chain of the hemoglobin molecule have stirred the curiosity of scientists and hematol-ogists for generations. When Linus Pauling discovered in 1949 that the altered hemoglobin migration pattern of sickle cell patients was due to a change in globin, the excitement among the scientific community was palpable. Dr. Pauling won The Nobel Prize for his discovery. Here was a description of the first molecular disease. Because proteins form the basis of the globin chain, there must be some abnormality in the chain to account for what was seen in the hemoglobin electrophoresis of sickle cell anemia individuals. Ingram et al.1 discovered the specific amino acid substitution located on the globin chain (valine substituted for glutamic acid or gluta-mine) and the specific abnormal codon responsible for this substitution has been characterized. In molecular terms, the nucleotide triplet guanine-adenine-guanine codes for the amino acid glutamine in the sixth position of the normal beta chain. In sickle cell patients, adenine is replaced by thymine coding for the amino acid valine. When valine is substituted for glutamine, an abnormal hemoglobin, hemoglobin S, is produced. Presently over 600 hemoglobin variants exist worldwide and most are beta chain disorders.2 To appreciate the magnitude of this statement, a brief review of the hemoglobin molecule is in order. All normal adult hemoglobins consist of two alpha chains, which have 141 amino acids in sequence, complemented by two non-alpha chains: beta, gamma, or delta. The non-alpha globin chains have 146 amino acids with amino acids linked together in sequence. Hemoglobinopathies occur as a result of one of four abnormal functions3:

1. A single amino acid substitution in one of the chains, usually the beta chain (i.e., sickle cell trait or disease)

2. Abnormal synthesis of one of the amino acid chains (i.e., thalassemia)

3. Fusion of hemoglobin chains (i.e., hemoglobin


4. Extension of an amino acid chain (i.e., hemoglobin Constant Spring)

Single amino acid substitutions in the beta chain account for most of the hemoglobinopathies that present with a hemolysis and clinical symptoms.

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