Splicing consequences of HNPCC associated MLH1 and MSH2 mutations
| Mutation | Family | Primary splicing effect | Frequency of mutant clones* | Number of clones studied for splicing | ||
|---|---|---|---|---|---|---|
| Total | Transcripts with extra splice events† | |||||
| Mutant | Normal | |||||
| *Among a representative number of clones (18–38) randomly selected for analysis of the predisposing defect. | ||||||
| †Among all clones known to be derived either from the mutation containing or normal allele. Note that even though the frequency of extra splice events in both types of transcripts is unbiased, relative proportion of mutation containing versus normal transcripts is not, since mutation containing clones, which were normally heavily underrepresented, were in some cases actively selected for analysis of splicing. | ||||||
| ‡p = 0.001 by Fisher’s exact test (2 tailed). | ||||||
| §A and G refer to the polymorphic base present at codon 219. | ||||||
| MLH1 | ||||||
| C→T at n 298, c 100, exon 3 (R100X) | 73 | None | 5/38 (13%) | 47 | 8/14 (57%)‡ | 3/33 (9%)‡ |
| Del AGAA at n 210, c 70, exon 3 | 95 | Δ3 (in frame) | 18/30 (60%) | 30 | 5/18 (28%) | 3/12 (25%) |
| C→T at n 975, c 659, exon 17 (R659X) | 83 | None | 1/31 (3%) | 32 | 0/2 (0%) | 2/19 (11%) |
| Δ17 (in frame) | 11/31 (35%) | 0/11 (0%) | ||||
| g→a at n 454-1, splice acceptor of exon 6 | 13 | Δ6 (out of frame) | 3/18 (17%) | 22 | 0/5 (0%) | 1/17 (6%) |
| Healthy control 1 | – | – | – | 11 (A)§ | – | 3/11 (27%) |
| 10 (G)§ | – | 0/10 (0%) | ||||
| Healthy control 2 | – | – | – | 12 (A)§ | – | 1/12 (8%) |
| 11 (G)§ | – | 2/11 (18%) | ||||
| MSH2 | ||||||
| C→T at n 1777, c 593, exon 12 (Q593X) | 65 | None | 1/32 (3%) | 32 | 0/1 (0%) | 0/31 (0%) |
| —with puromycin | 2/17 (12%) | 17 | 0/2 (0%) | 2/15 (13%) | ||
| Ins GT at n 1860, c 620, exon 12 | 25 | None | 3/40 (8%) | 40 | 0/3 (0%) | 1/37 (3%) |
| Del CA at n 1550, c 518, exon 10 | 38 | None | 1/35 (3%) | 35 | 0/1 (0%) | 0/34 (0%) |
| Healthy control 1 | – | – | – | 24 | – | 0/24 (0%) |