FMR1 (Fra X Mental Retardation 1), a gene of unknown function, is resp
onsible for an important hereditary mental retardation, the fragile X
syndrome. In this study, a 22-bp enhancer (methylation sensitive eleme
nt, MSE) in the FMR1 promoter was defined by DNase I footprinting assa
y, and the binding of this element by nuclear factor was prevented by
DNA CpG methylation. A cAMP-responsive element (CRE)-like sequence and
a myc-binding sequence in MSE were identified. In the transfection as
say, MSE demonstrated a strong, methylation-sensitive enhancer activit
y. MSE could be bound by recombinant CRE-binding protein (CREB), and i
ts activity was stimulated by CREB in a co-transfection assay. In PC12
cells, forskolin elevated MSE activity several fold, and this inducti
on was abolished in CRE mutants. The involvement of cAMP in the expres
sion of FMR1 should be a clue to both the function of FMR1 and the pat
hogenesis of fragile X syndrome.