Molecular basis for nondeletion alpha-thalassemia in American blacks. Alpha 2(116GAG----UAG).
An American black woman was found to have the phenotype of moderately severe alpha-thalassemia normally associated with the loss of two to three alpha-globin genes despite an alpha-globin gene map that demonstrated the loss of only a single alpha-globin gene (-alpha/alpha alpha). Several individuals in her kindred with normal alpha-globin gene mapping studies (alpha alpha/alpha alpha) had mild alpha-thalassemia hematologic values consistent with the loss of one to two alpha-globin genes. These data suggested the presence of a nondeletion alpha-thalassemia defect in this family which segregates with the intact alpha alpha gene cluster. An abnormally migrating and highly unstable alpha-globin gene product was demonstrated by in vitro translation of the reticulocyte mRNA from the proposita and this mutant alpha-globin protein was mapped to the alpha 2-globin gene by hybrid-selected translation. The abnormal alpha 2-globin gene was cloned and sequenced. A single base mutation that results in a premature termination codon was identified at codon 116 (GAG----UAG). The defined alpha-globin genotype of the proposita (-alpha/alpha 116UAG alpha) and the positioning of this nonsense mutation at the alpha 2-globin gene locus are fully consistent with the observed alpha-thalassemia phenotype.
D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D044383:Black People; D003001:Cloning, Molecular; D003062:Codon; D005260:Female; D005838:Genotype; D005914:Globins / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D013789:Thalassemia / Q000235:genetics*
D003062:Codon; D012333:RNA, Messenger; D005914:Globins