Missense and nonsense mutations in codon 659 of MLH1 cause aberrant splicing of messenger RNA in HNPCC kindreds

Germline mutations that give rise to premature termination codons in mRNAs have frequently been associated with aberrant processing of the nascent tra nscripts. This can take the form either of nonsense-mediated mRNA decay or of aberrant splicing of the pre-mRNA. In a family affected by hereditary no npolyposis colorectal cancer, a Mo-nucleotide deletion in codon 659, which introduces a frameshift and a new stop codon in exon 17 of the DNA mismatch repair gene MU-I I, has been reported to lead to skipping of the exon. We now report that this phenomenon occurs also when there are missense or nons ense mutations in this codon. Our results thus suggest that in aberrant spl icing the nature of the mutation may be less important than its position wi thin the exon. These findings are of importance to mutation interpretation, as they imply that aberrant splicing could be associated even with silent mutations that do not lead to amino acid substitutions. (C) 1999 Wiley-Liss , Inc.