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Nucleic Acids Research, 1994, Vol. 22, No. 8 1327-1334
© 1994

SURVEY AND SUMMARY

Mutations to nonsense codons in human genetic disease: implications for gene therapy by nonsense suppressor tRNAs

Jennifer Atkinson and Robin Martin*

Krebs Institute for Biomolecular Research, The University of Sheffield PO Box 594, Firth Court, Western Bank, Sheffield S10 2UH, UK

*To whom correspondence should be addressed

Received January 28, 1994. Revised March 7, 1994. Accepted March 7, 1994.

Nonsense suppressor tRNAs have been suggested as potential agents for human somatic gene therapy. Recent work from this laboratory has described significant effects of 3' codon context on the efficiency of human nonsense suppressors. A rapid increase in the number of reports of human diseases caused by nonsense codons, prompted us to determine how the spectrum of mutation to either UAG, UAA or UGA codons and their respective 3' contexts, might effect the efficiency of human suppressor tRNAs employed for purposes of gene therapy. This paper presents a survey of 179 events of mutations to nonsense codons which cause human germline or somatic disease. The analysis revealed a ratio of approximately 1:2:3 for mutation to UAA, UAG and UGA respectively. This pattern is similar, but not identical, to that of naturally occurring stop codons. The 3' contexts of new mutations to stop were also analysed. Once again, the pattern was similar to the contexts surrounding natural termination signals. These results imply there will be little difference in the sensitivity of nonsense mutations and natural stop codons to suppression by nonsense suppressor tRNAs. Analysis of the codons altered by nonsense mutations suggests that efforts to design human UAG suppressor tRNAs charged with Trp, Gin, and Glu; UAA suppressors charged with Gin and Glu, and UGA suppressors which insert Arg, would be an essential step in the development of suppressor tRNAs as agents of human somatic gene therapy.


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