title: A novel beta-globin mutation, beta Durham-NC [beta 114 Leu-->Pro], produces a dominant thalassemia-like phenotype.
abstract: Mutations within exon 3 of the beta-globin gene are relatively uncommon, and many of these mutations produce a dominant thalassemia-like phenotype. We describe a novel thalassemic hemoglobinopathy caused by a single nucleotide substitution (CTG-->CCG) at codon 114 resulting in a leucine to proline substitution and designate it beta Durham-NC [beta 114 Leu-->Pro]. The mutation producing this thalassemic hemoglobinopathy is located near to the beta Showa-Yakushiji mutation (beta 110 Leu-->Pro). Both of these hemoglobinopathies share similar phenotypic features with moderately severe microcytic anemia. Using computer imaging of the hemoglobin molecule, we examined several reported point mutations within exon 3 of the beta-globin gene. These point mutations cause a single amino acid substitution in the G helix, and result in a thalassemic and/or hemolytic phenotype. Computer imaging of nine separate examples suggests that amino acid substitutions affecting side chains that project into the heme pocket may destabilize the heme moiety within the beta-globin chain, resulting in a thalassemic phenotype. Hemolytic phenotypes may be the result of decreased alpha 1 beta 1 interactions. The beta Durham-NC mutation further characterizes a novel group of thalassemias/hemoglobinopathies that are clinically difficult to identify and require accessory laboratory testing.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: C M
authors.initials: CM
authors.lastname: de Castro
authors.forename: B
authors.initials: B
authors.lastname: Devlin
authors.forename: D E
authors.initials: DE
authors.lastname: Fleenor
authors.forename: M E
authors.initials: ME
authors.lastname: Lee
authors.forename: R E
authors.initials: RE
authors.lastname: Kaufman
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D003062:Codon; D003196:Computer Graphics; D004247:DNA / Q000097:blood / Q000302:isolation & purification; D017931:DNA Primers; D004912:Erythrocytes / Q000378:metabolism*; D005091:Exons; D005260:Female; D005914:Globins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007930:Leucine; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction / Q000379:methods; D011392:Proline; D017433:Protein Structure, Secondary; D013789:Thalassemia / Q000097:blood / Q000235:genetics*
chemical_list: D003062:Codon; D017931:DNA Primers; D005914:Globins; D004247:DNA; D011392:Proline; D007930:Leucine