Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the β-globin gene

Haig H. Kazazian, Carol E. Dowling, Richard L. Hurwitz, Morton Coleman, Alison T Stopeck, Junius G. Adams

Research output: Contribution to journalArticle

61 Citations (Scopus)

Abstract

Mutations producing β-thalassemia reach individual gene frequencies greater than .01 in malarial-endemic regions because β-thalassemia trait individuals have increased genetic fitness over that of normal individuals. Exon 3 of the β-globin gene has been relatively spared as a site of common β-thalassemia mutations. Frameshifts caused by the loss of a single nucleotide and nonsense mutations produce β-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 β-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 (βManhattan) that is elongated to 156 amino acids. The second is a CAG-CGG missense mutation at codon 127 that causes a Gln → Pro substitution (βHouston) 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 β-globin to form αβ 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.

Original languageEnglish (US)
Pages (from-to)3014-3018
Number of pages5
JournalBlood
Volume79
Issue number11
StatePublished - Jun 1 1992
Externally publishedYes

Fingerprint

Thalassemia
Globins
Exons
Genes
Phenotype
Mutation
Genetic Fitness
beta-Thalassemia
Hemolytic Anemia
Missense Mutation
Hemolysis
Codon
Nucleotides
Aptitude
Nonsense Codon
Heterozygote
Gene Frequency
Dimers
Malaria
Substitution reactions

ASJC Scopus subject areas

  • Hematology

Cite this

Kazazian, H. H., Dowling, C. E., Hurwitz, R. L., Coleman, M., Stopeck, A. T., & Adams, J. G. (1992). Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the β-globin gene. Blood, 79(11), 3014-3018.

Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the β-globin gene. / Kazazian, Haig H.; Dowling, Carol E.; Hurwitz, Richard L.; Coleman, Morton; Stopeck, Alison T; Adams, Junius G.

In: Blood, Vol. 79, No. 11, 01.06.1992, p. 3014-3018.

Research output: Contribution to journalArticle

Kazazian, HH, Dowling, CE, Hurwitz, RL, Coleman, M, Stopeck, AT & Adams, JG 1992, 'Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the β-globin gene', Blood, vol. 79, no. 11, pp. 3014-3018.
Kazazian HH, Dowling CE, Hurwitz RL, Coleman M, Stopeck AT, Adams JG. Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the β-globin gene. Blood. 1992 Jun 1;79(11):3014-3018.
Kazazian, Haig H. ; Dowling, Carol E. ; Hurwitz, Richard L. ; Coleman, Morton ; Stopeck, Alison T ; Adams, Junius G. / Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the β-globin gene. In: Blood. 1992 ; Vol. 79, No. 11. pp. 3014-3018.
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