Analysis of aneuploidy frequencies in sperm from patients with hereditary nonpolyposis colon cancer and an hMSH2 mutation

Hereditary nonpolyposis colon cancer (HNPCC) has been shown to be caused by mutations in the mismatch repair genes hMSH2, hMLH1, hPMS1, and hPMS2. Rec ent evidence has demonstrated that mutations in mismatch repair genes disru pt meiosis in mice. A large HNPCC kindred in Newfoundland, Canada, has an h MSH2 mutation-an A-->T transversion at the +3 position of the splice-donor site of exon 5. We have studied sperm from men with this hMSH2 mutation, si nce it is possible that mismatch repair mutations in humans might also have an effect on meiosis and normal segregation of chromosomes. The frequencie s of aneuploid and diploid sperm were determined in 10 men with the hMSH2 m utation, by use of multicolor FISH analysis for chromosomes 13, 21, X, and Y. A minimum of 10,000 sperm per man was studied per chromosome probe. Cont rol individuals consisted of men in the same kindred with HNPCC who did not carry the mutation and of other normal men from Newfoundland, A total of 3 21,663 sperm were analyzed: 200,905 sperm were from men carrying the hMSH2 mutation and 120,758 sperm were from control men, There was a significantly increased frequency of disomy 13, disomy 21, XX, and diploidy in mutation carriers compared with control men. These results suggest that the hMSH2 mu tation may affect meiosis in humans.