Deletions in the CGG repeat region of the FMR1 gene
- Erasmus Univ., Rotterdam (Netherlands)
- and others
The fragile X syndrome is the most frequent cause of inherited mental retardation. A remarkable feature of FMR1, the gene involved in the fragile X syndrome, is the presence of a polymorphic (CGG){sub n} repeat in the first exon of the gene. In patients this repeat is expanded to over 200 repeats. The expansion results in methylation of the CpG island 250 bp upstream of this repeat, leading to the absence of FMR1 mRNA and protein, thus resulting in the fragile X phenotype. We have found that the instability of the repeat is not restricted to the CGG repeat itself but expands to the flanking region as well. Firstly, we have identified a family in which 4 males with the fragile X clinical phenotype had a deletion immediately 5{prime} of the CGG repeat. Sequencing the deletion junction revealed that the AGG triplets that normally intersperse the CGG repeat were lacking. This suggests that prior to the deletion an expansion of the repeat had occured. The male patients with this deletion did not have FMR1 mRNA expression. The deceased grandfather, from whom the deletion originated, was fertile, despite the lack of FMR1 mRNA expression. This indicated that FMR1 expression is not required for spermatogenesis. Other deletions were found in 4 individual patients. These patients were mosaic for both a full mutation and a small deletion in the region surrounding the (CGG){sub n} repeat, present in approximately 5% of their cells. Sequence analysis of the regions surrounding the deletions showed that the (CGG){sub n} repeat was missing in all 4 patients. The 5{prime} endpoints of all deletions were found to be located between 75 to 53 bp proximal to the CGG repeat. This suggests a hot spot region for deletions and emphasizes the instability of this region when the CGG repeat is expanded. Models explaining the occurrence of the deletions will be discussed.
- OSTI ID:
- 134197
- Report Number(s):
- CONF-941009--
- Journal Information:
- American Journal of Human Genetics, Journal Name: American Journal of Human Genetics Journal Issue: Suppl.3 Vol. 55; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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