title: Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the beta-globin gene.
abstract: 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.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: H H
authors.initials: HH
authors.lastname: Kazazian
authors.forename: C E
authors.initials: CE
authors.lastname: Dowling
authors.forename: R L
authors.initials: RL
authors.lastname: Hurwitz
authors.forename: M
authors.initials: M
authors.lastname: Coleman
authors.forename: A
authors.initials: A
authors.lastname: Stopeck
authors.forename: J G
authors.initials: JG
authors.lastname: Adams
mesh_terms: D000368:Aged; D001483:Base Sequence; D002872:Chromosome Deletion; D003062:Codon; D005091:Exons; D005260:Female; D005914:Globins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D013789:Thalassemia / Q000235:genetics*
chemical_list: D003062:Codon; D005914:Globins