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Dominant thalassemia-like phenotypes associated with mutations in exon 3 of
the beta-globin gene
HH Kazazian , CE Dowling, RL Hurwitz, M Coleman, A Stopeck and JG Adams
Department of Pediatrics, Johns Hopkins University School of Medicine,
Baltimore, MD 21205.
Mutations producing beta-thalassemia reach individual gene frequencies
greater than .01 in malarial-endemic regions because beta-thalassemia trait
individuals have increased genetic fitness over that of normal individuals.
Exon 3 of the beta-globin gene has been relatively spared as a site of
common beta-thalassemia mutations. Frameshifts caused by the loss of a
single nucleotide and nonsense mutations produce beta- thalassemia trait
when they occur in exons 1 and 2. In contrast, they usually produce chronic
hemolytic anemia when present in exon 3. Certain missense mutations in exon
3 produce unstable globins and thalassemia intermedia with hemolysis in
heterozygotes. Here we report two new mutations in exon 3 of the
beta-globin gene. One is a single nucleotide deletion in codon 109 in a
78-year-old Lithuanian with chronic hemolytic anemia and features of
thalassemia. It leads to an abnormal globin (beta Manhattan) that is
elongated to 156 amino acids. The second is a CAG-CGG missense mutation at
codon 127 that causes a Gln----Pro substitution (beta Houston) and a
thalassemia intermedia with hemolysis in three generations of a
British-American family. Although the clinical phenotypes of these two
patients differed little, differences in globin-synthetic ratios were
significant, presumably reflecting differences in the ability of each
abnormal beta-globin to form alpha beta dimers. The paucity of
high-frequency exon 3 mutations and their worldwide distribution is likely
attributable to their phenotypic severity and loss of increased genetic
fitness vis-a-vis malaria.
Volume 79,
Issue 11,
pp. 3014-3018,
06/01/1992
Copyright © 1992 by The American Society of Hematology
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