Reduced cyclic AMP production in fragile X syndrome: Cytogenetic and molecular correlations

The cAMP cascade is an intracellular signal transduction system thought to be important for neuronal regulation and information storage. cAMP production is reduced in platelets from patients with fragile X syndrome. In the present study we assayed cAMP metabolism, Xq27.3 fragile site percentages, size of amplification mutation in fragile X mental retardation-1 gene (FMR-1), and FMR-1 mRNA levels in 21 lymphoblastoid cell lines (LCL) from fragile X patients. cAMP production was diminished in fragile X LCL relative to controls (n = 20) when cells were assayed in prostaglandin Et (74%, p < 0.02) and in forskolin (64%, p < 0.1) although the difference was statistically significant only in prostaglandin Ex. The length of the FMR-1 amplification mutation correlated with measures of cAMP production which were unassociated with receptor activation (r = -0.53, p = 0.02, and r = -0.48, p = 0.03, for unstimulated and forskolin-stimulated cAMP production, respectively). In fragile X LCL, fragile site percentages did not correlate with any measure of cAMP production. All fragile X LCL showed absence of FMR-1 mRNA. These data suggest that diminished cAMP production in fragile X tissues may be linked to the fragile X amplification mutation, either as a result of influences of the mutation on FMR-1 expression or on transcription of other genes downstream from FMR-1.