'Silent' nucleotide substitution in a β+-thalassemia globin gene activates splice site in coding sequence RNA

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

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

A β+-thalassemia globin gene was isolated from the genome of a Black individual by molecular cloning. DNA sequence analysis revealed only a single difference between this gene and the normal human β-globin gene-adenine is substituted for thymine in the third position of codon 24. Codon 24 in both the normal gene (GGT) and the β+-thalassemia gene (GGA) encodes glycine. The function of this β+-thalassemia gene was compared to the function of the normal human β-globin gene in monkey kidney cells by 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. The splice, involving the abnormal 5' site in codon 25, is completed with the normal 3' splice site at the end of intron I. This splicing abnormality leads to a 75% decrease in the accumulation of normally processed β-globin mRNA, thereby causing the β+-thalassemia phenotype.

Original languageEnglish
Pages (from-to)2318-2322
Number of pages5
JournalUnknown Journal
Volume80
Issue number8 I
DOIs
StatePublished - 1983

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