Reduced Cyclic AMP Production in Fragile X Syndrome: Cytogenetic and Molecular Correlations

Abstract

ABSTRACT: 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 E₁ (74%, p < 0.02) and in forskolin (64%, p < 0.1) although the difference was statistically significant only in prostaglandin E₁. 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.

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