Evidence that fragile X gene (FMR-1) instability occurs within the 3{prime} end of the triplet repeat region
- NYS Institute for Basic Research, NY (United States); and others
Expansion of the CGG repeat in the 5{prime} untranslated region of the FMR-1 gene results in methylation of the upstream CpG island, lack of gene expression and the fragile X phenotype. Interspersed AGGs within the CGG repeat region may stabilize the sequence and prevent slippage during DNA replication. This hypothesis has been difficult to test due to sequencing difficulties. We have developed a method to detect and analyze the AGG variation within the CGG repeat region using PCR amplification and partial Mnl I restriction analysis. We analyzed 74 control X chromosomes with a range of 20 to 52 triplet repeat lengths. Results showed that the position of interspersed AGGs was highly polymorphic with heterozygosity of >95%. 68% of alleles had 2 AGGs, usually separated by 9 or 10 CGGs. Of 17 alleles with {le}26 repeats, 12% had no AGG, 76% had one and 12% had two. Of 13 alleles with {ge}35 repeats, 8% had one AGG, 62% had two and 31% had three. Of the 74 control samples overall, 24.3% had {ge}15 uninterrupted CGGs. 14.7% had {ge}20 and 2.7% had {ge}30. Of those with {ge}15 pure CGGs, 94% were within the 3{prime} end. A comparison of these controls with premutation alleles suggests that high variability and instability of CGGs nearly always occurs within the 3{prime} end of the FMR-1 triplet repeat. Finally, there was a significant association between the presence of a long pure CGG region ({ge}15) and FRAXAC1 alleles of type 20 and 21, similar to our previous results with fragile X chromosomes. We hypothesize that like fragile X alleles, normal sized alleles with long uninterrupted repeat regions may induce flanking microsatellite mutations by a mechanism such as unequal gene conversion leading to increased marker variability, which may mimic founder effects.
- OSTI ID:
- 134373
- 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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