Around one-third of all disease mutations in humans cause premature termination of translation. So if there was a way to find transcripts in a cell that carry such mutations, then that would be a powerful tool for diagnosing the genetic cause of any disease. Noensie and Dietz have devised an elegant method that is close to achieving this.

Cells normally degrade any message that contains a premature termination codon, introduced for example by a nonsense or frameshift mutation. This surveillance mechanism — nonsense-mediated mRNA decay (NMD) — is thought to protect cells from the potentially deleterious effects of truncated proteins. Noensie and Dietz reasoned that inhibition of NMD would therefore increase the abundance of transcripts that contain premature termination codons.

NMD is a response to stalled ribosomes and so is dependent on translation. To inhibit NMD, the authors therefore used inhibitors of translation. Not surprisingly, the inhibitors affect the level of some transcripts whether or not they contain a nonsense mutation, but this background can be reduced by judicious use of controls. Microarrays are then used to detect transcripts whose rise in abundance is caused by inhibition of NMD rather than by some other effect of the inhibitor.

The method was validated in two cell lines, each carrying a single nonsense mutation. Around 5,000 genes were screened, and a list of genes that increase in abundance in the presence of the inhibitor was obtained for each line. The target genes were 19th and 48th on the two lists — so the method isn't perfect. However, when you consider the location of the genes, or information about their function, the target genes stand out as much stronger candidates. In a News and Views article, Mike Culbertson concludes that the method has broad implications for genetic disease research and could be valuable for positional cloning projects.