"Silent" nucleotide substitution in codon 24 of a beta+ thalassemia globin gene activates splice site in coding sequence RNA.

R. K. Humphries, T. Ley, M. E. Goldsmith, J. A. Kantor, A. C. Cline, A. W. Nienhuis

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Pages (from-to)123-126
Number of pages4
JournalProgress in Clinical and Biological Research
Volume134
StatePublished - Dec 1 1983

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