Human Molecular Genetics, Vol 8, 2293-2302, Copyright © 1999 by Oxford University Press
RW Burman, BW Popovich, PB Jacky and MS Turker
The fragile X syndrome is characterized at the molecular level by expansion
and methylation of a CGG trinucleotide repeat located within the FMR1
locus. The tissues of most full mutation carriers are mosaic for repeat
size, but these mutational patterns tend to be well conserved when
comparing multiple tissues within an individual. Moreover, full mutation
alleles are stable in cultured fibroblasts. These observations have been
used to suggest that fragile X CGG repeat instability normally is limited
to a period during early embryogenesis. DNA methylation of the repeat
region is also believed to occur during early development, and some
experimental evidence indicates that this modification may stabilize the
repeats. To study the behavior of full mutation alleles in mitotic cells,
we generated human-mouse somatic cell hybrids that carry both methylated
and unmethylated full mutation FMR1 alleles. We observed considerable
repeat instability and analyzed repeat dynamics in the hybrids as a
function of DNA methylation, repeat length and cellular differentiation.
Our results indicate that although DNA methylation does correlate with
stability in primary human fibroblasts, it does not do so in the cell
hybrids. Instead, repeat stability in the hybrids is dependent on repeat
length, except in an undifferentiated cellular background where large
alleles are maintained with a high degree of stability. This stability is
lost when the cells undergo differentiation. These results indicate that
the determinants of CGG repeat stability are more complex than generally
believed, and suggest an unexpected role for cellular differentiation in
this process.
ARTICLES
Fully expanded FMR1 CGG repeats exhibit a length- and differentiation- dependent instability in cell hybrids that is independent of DNA methylation
Department of Molecular and Medical Genetics,
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