title: "Silent" nucleotide substitution in codon 24 of a beta+ thalassemia globin gene activates splice site in coding sequence RNA.
abstract: A beta+-thalassemia globin gene was isolated from the genome of a black patient by molecular cloning. DNA sequence analysis revealed only a single difference between this gene and the normal human beta-globin gene--adenine is substituted for thymine in the third position of codon 24. This mutation is silent at the protein sequence level. We compared the function of this beta+-thalassemia gene with the normal human beta-globin gene in monkey kidney cells using plasmid expression vectors. The codon 24 substitution activates a 5' splice site that involves the guanine-thymine dinucleotide present in codon 25, 16 nucleotides upstream from the normal exon 1-intron I boundary. Splices at the abnormal 5' site in the coding sequence are completed with the normal 3' splice site at the end of intron I. This splicing abnormality leads to a fourfold decrease in the accumulation of normally processed beta-globin mRNA, thereby causing the beta+-thalassemia phenotype.
mesh_terms: D001483:Base Sequence; D003001:Cloning, Molecular; D003062:Codon; D005796:Genes; D005914:Globins / Q000235:genetics*; D006801:Humans; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D013789:Thalassemia / Q000235:genetics*
chemical_list: D003062:Codon; D012333:RNA, Messenger; D005914:Globins