22 research outputs found
Elevated Fmr1 mRNA levels and reduced protein expression in a mouse model with an unmethylated Fragile X full mutation
The human FMR1 gene contains a CGG repeat in its 5′ untranslated region. The repeat length
in the normal population is polymorphic (5–55 CGG repeats). Lengths beyond 200 CGGs (full
mutation) result in the absence of the FMR1 gene product, FMRP, through abnormal
methylation and gene silencing. This causes Fragile X syndrome, the most common
inherited form of mental retardation. Elderly carriers of the premutation, defined as a repeat
length between 55 and 200 CGGs, can develop a progressive neurodegenerative syndrome:
Fragile X-associated tremor/ataxia syndrome (FXTAS). In FXTAS, FMR1 mRNA levels are
elevated and it has been hypothesised that FXTAS is caused by a pathogenic RNA gain-offunction
mechanism. We have developed a knock in mouse model carrying an expanded
CGG repeat (98 repeats), which shows repeat instability and displays biochemical,
phenotypic and neuropathological characteristics of FXTAS. Here, we report further
repeat instability, up to 230 CGGs. An expansion bias was observed, with the largest
expansion being 43 CGG units and the largest contraction 80 CGG repeats. In humans, this
length would be considered a full mutation and would be expected to result in gene
silencing. Mice carrying long repeats (∼230 CGGs) display elevated mRNA levels and
decreased FMRP levels, but absence of abnormal methylation, suggesting that modelling the
Fragile X full mutation in mice requires additional repeats or other genetic manipulation