Rearrangements in the flanking sequences of the triplet repeat of the FMR1 gene give clues to the mechanisms involved in repeat instability in fragile X.

摘要

We wish to comment on the article by Kosmider and Wells entitled 'Fragile X repeats are potent inducers of complex, multiple site rearrangements in flanking sequences in Escherichia coli'. When studying the mutagenic effect of CGG~*CCG repeats in their model system, the authors unexpectedly found that some mutant clones contained deletions, inversions, and insertions and some contained only gross deletions in the triplet repeats as well as in DNA sequences which flank the repeats.We would like to point out that we have recently reported on a novel duplication in the human FMR1 gene: a 49 bp tandem duplication found adjacent to the triplet repeat, which contained 31 repeats. We have suggested that the duplication has arisen by a misalignment of the proximal end of the repeat tract and the non-adjacent GGCGGCGGCGG-sequence located 37 bp upstream and may indicate a mutation hot spot. We have concluded that the discovery of this duplication and the previous observations on deletions associated with full mutations in patients with fragile X syndrome indicate that realignment between the repeat tract and dispersed non-adjacent homologous repetitive sequences may also play a role in repeat instability in fragile X-which supports the interesting data and the molecular mechanisms possibly involved in the mutagenic spectrum of the fragile X syndrome presented by Kosmider and Wells. Furthermore, a tandem duplication model has been published that potentially accounts for the duplication event we have observed.