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A Rapid Screening Method to Detect Nonsense and Frameshift Mutations: Identification of Disease-causing APC Alleles¹

Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy [L. V., V. G., G. B. F.], and Howard Hughes Medical Institute [J. G., M. R., R. Wh.] and Department of Human Genetics [L. S., R. W., R. Wh.], Eccles Institute of Human Genetics, The University of Utah, Salt Lake City, Utah 84112

² Present address: Department of Molecular Genetics, Biochemistry and Microbiology, The University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524. To whom requests for reprints should be addressed.

A functional screen for nonsense and frameshift mutations has been devised that allows genes of interest to be scanned in segments. This assay is based on the cloning of these segments in-frame with a colorimetric marker gene (lacZ) followed by screening for the level of functional activity from the marker polypeptide (β-galactosidase). Individuals at risk for any one of a number of genetic diseases, in particular familial adenomatous polyposis coli (APC), can be quickly screened for chain-terminating mutations introduced by stops and frameshifts. At present, scanning of the APC gene for mutation requires significant effort because it is a large gene and most APC mutations are unique. Therefore, this assay offers a powerful option for the diagnosis of this and other genetic diseases, as well as great potential for the development of a similar rapid screen to detect APC mutations in colorectal adenomas and carcinomas.

¹ This work was supported by the Howard Hughes Medical Institute, NIH Grant 5P30-HG00199-03, the Associazione Italiana Ricerca sul Cancro, C.N.R. Target Project "Biotechnology and Bioinstrumentation" Contract N. 93.0110PF70, and C.N.R. Progetto Finalizzato Ingegneria Genetica Contract N. 93.00050.PF99.

³ Investigator of the Howard Hughes Medical Institute.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/29/93. Accepted 10/20/93.

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