Gene copy-editing error causes cancer

Lynch syndrome is caused by mutations in genes encoding DNA repair proteins. Geneticists had previously found that all the mutations lie within protein-coding regions of the genes or at splice sites that direct the removal of non-coding regions before protein synthesis. Now, however, a research team led by Mark Clendenning of the Queensland Institute of Medical Research, Australia, has identified a novel mutation mechanism¹.

Clendenning and his colleagues collected tumor and blood samples from seven members of the same Australian family with Lynch syndrome, and sequenced the DNA from the samples using standard protocols. Since they failed to find any mutations, they used an alternative procedure for detecting mutations. They identified a disease-causing mutation deep within a non-coding region of the MSH2 gene, which encodes a protein that repairs DNA that has been replicated incorrectly.

The mechanism produces a novel splice site between the first and second coding regions, which leads to the synthesis of a non-functional protein. A similar mechanism has previously been shown to cause mutations in cystic fibrosis, but has never been highlighted before in Lynch syndrome.

The findings emphasize the importance of analyzing DNA sequences more extensively to identify mutations that are not found using standard methods.