Overexpression of fragile X gene (FMR-1) transcripts increases cAMP production in neural cells

Fragile X syndrome results from amplification of an unstable trinucleotide (CGG) repeat in the first exon of FMR-1, the "fragile X gene." This mutation silences the gene, resulting in loss of expression of the FMR proteins (FMRP), a series of RNA-binding proteins generated by alternative splicing of FMR-1 transcripts. We have shown that cAMP production is diminished in cells from patients with fragile X syndrome. To establish a direct relationship between FMR-1 expression and cAMP metabolism, FMRP isoforms 1 and 7 were overexpressed in the neurotumor hybrid cell line HN2. Cyclic AMP production in clonal HN2 lines overexpressing FMRP was significantly higher than in nonoverexpressing control lines and increased with increasing total FMR-1 mRNA on Northern blots and FMRP signal on Western blots. These data support a role for FMRP in the regulation of cAMP signal transduction by increasing intracellular cAMP, perhaps through a mechanism involving binding and enhanced translation of mRNA(s) for cAMP cascade proteins. Diminished cAMP production in the absence of FMR-1 may provide one neurochemical mechanism through which FMR-1 influences cognitive function.