Globin Mutants

The y- and 5-chain mutants are difficult to study because of the small fraction of HbF and HbA2 present in adult erythrocytes. Overt clinical symptoms associated with y- and 5-chain variants are rare. By routine screening, 14 5-globin variants have been discovered but are of no clinical consequence. Thirty-five mutant y sequences (involving the Gy or the Ay chains) have been identified. They are all benign except for HbF Poole [Gyl30(H8) Tyr — Gly], an unstable hemoglobin that causes hemolytic disease in the newborn. 

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Sickle cell anemia Human P-globin mutant 11, 12... 

Other a-globin mutants have a mutation at the intron-exon boundary (mRNA splice boundary) that prevents RNA processing or a mutation in the recognition sequence needed for polyadenylation of the mRNA during RNA maturation. In other a+-thalassemias with both a genes present but active only at a reduced level, the defect has not been identified. 

P-Thalassemla (MIM 141900) A very wide variety of mutations in the p-globin gene, including deletions, nonsense and frameshift mutations, and others affecting every aspect of its structure (eg, splice sites, promoter mutants)... 

RFLP analysis of the p-globin gene for genetic testing has been replaced, by PCR In combination with ASO probes on dot blots. The blot shown here corresponds to the family whose pedigree is shown in Figure T7-9. In the mutant allele, glutamate (E) at codon 6 is replaced by valine (V). 

The answer is B. Sickle cell anemia is caused by inheriting two copies of a mutant P glo-bin gene that leads to synthesis of sickle hemoglobin, HbS. A severe case of sickle cell anemia would most likely have demonstrated symptoms and been diagnosed before the age of 6. However, he may only be a carrier, with one copy each of normal P-globin and one of the sickle allele, a condition called sickle cell trait. Nevertheless, the patient s... 

A one-year-old male with chronic anemia is found to have (B-thalassemia. Genetic analysis shows that one of his (B-globin genes has a G to A mutation that creates a new splice acceptor site nineteen nucleotides upstream from the normal splice acceptor site of the first intron. Which of the following best describes the new messen ger RNA molecule that can be produced from this mutant gene ... 

A MALDI-TOF mass spectrum of human hemoglobin Hb Miyazono. Two p-globins (one normal and one mutant) are detected. B MALDI spectrum of the tryptic cleavage of the (3-globin from Hb Miyazono mutant of human hemoglobin. Mutated peptides T9m and T8+T9m are detected. By tandem mass spectrometry, the mutation is characterized as the substitution 79D-E. Reproduced (modified) from Wada Y., Journal of Chromatography B, 781, 291-301, 2002, with permission. 

The term hemoglobinopathies refers to hemoglobin disorders caused by normal synthesis of qualitatively abnormal globin chains. Transcription and translation of mutant genes usually proceed at a normal rate, but the products denature rapidly or function abnormally. 

A selected list of mutant hemoglobins is given in Table 28-5. The most common mutations are the single-amino-acid substitutions caused by one nucleotide change in a globin gene. The table also lists several deletion mutations and one nonsense mutation. Globin chains that contain two mutations are extremely rare and appear to have resulted from a second mutation in a common mutant (usually HbS or HbC). 

Peterson, K. R., Li, Q.-L., Clegg, C. H., Furukawa, T., Navas, P. A., Norton, E. J., Kimbrough, T. G., and Stamatoyannopoulos, G. 1995. Use of yeast artificial chromosomes (YACs) in smdies of mammalian development prodnction of 3-globin locus YAC mice carrying hnman globin developmental mutants, Proc. Natl. Acad. Sci. U.S.A., 92, 5655-5659. 

Each of the mutant forms of hemoglobin exists in only a small fraction of the total human population. Many of the mutant forms are deleterious. Others appear to be harmless, and are often referred to as neutral mutations. A very few may have advantages. Inheritance of globin genes occurs as a result of standard genetic processes (see here for a review of genetics). 

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