In a family of northern Italian descent (Brescia-Lombardia), Murru et al. (1992) found that a 14-year-old girl with the clinical phenotype of severe thalassemia intermedia (613985) had a heterozygous CTG-to-CCG change at codon 114 resulting in substitution of proline for leucine in the beta-globin chain. The resulting hemoglobin tetramer was highly unstable and precipitated to form inclusion bodies in peripheral red blood cells. The unusually severe phenotype present in this heterozygote was thought to be explained by the coinheritance of a triple alpha-globin locus.
In a 29-year-old female of Irish descent with thalassemia-like anemia during her first pregnancy, deCastro et al. (1992) found no gross structural alteration on Southern blot analysis of the globin genes but found an alpha:beta globin chain synthesis ratio of 0.91 (control = 0.94). Because they suspected an unstable hemoglobinopathy and because many of these disorders are due to point mutations in exon 3 of the beta-globin chain, they performed PCR-SSCP analysis, which showed an abnormality. Sequencing demonstrated a T-to-C transition at codon 114 resulting in a leucine-to-proline substitution. They called the hemoglobin variant Durham-N.C. to distinguish it from hemoglobin Durham, named for the city in England. The mutation created a novel MspI restriction site in exon 3 of the HBB gene. De Castro et al. (1994) demonstrated that this hemoglobinopathy, like several others within exon 3 of the beta-globin gene, e.g., Hb Showa-Yakushiji (leu110-to-pro; 141900.0262), result in a thalassemic and/or hemolytic phenotype with moderately severe microcytic anemia inherited as an autosomal dominant.
Kim et al. (2001) described the molecular and hematologic characteristics of a Korean family with a dominantly inherited beta-thalassemia. Carriers were characterized by moderate anemia, hypochromia, microcytosis, elevated Hb A2 and Hb F levels, and splenomegaly. A CTG (leu) to CCG (pro) change at codon 114 of the HBB was demonstrated. They referred to the abnormal hemoglobin as Hb Durham-N.C./Brescia.
