Study On The Coadjustment Effect Of FMR1 Gene And CAMP

The fragile X syndrome [Fra(X)] is one of the most common inherited form of mental retardation (MR). A gene named fragile X mental retardation 1(FMR1) which located in the band q27.3 of X chromosome has been found answering for this syndrome. In most cases,Fra(X) is associated with an unstable expansion of the CGG trinucleotide repeat in the 5' UTR of exon 1 and abnormal methylation of the CpG island in the promter region of the FMR1 gene. The primary character and deformity causing factor of this desease is variable degrees of MR,whose mechanism hasn't been found at all. Studies of modern Neurobiology has proved that cAMP level in the neuron is associated with mental activities such as learning and memory. Studies have shown that the cAMP level reduced in the affected cells of Fra(X). So the intracellular cAMP level reduction might be the physiological foundation of MR. This study aims at discussing the mechanism of the intracellular cAMP reduction of Fra(X) and the possible gene-regulate effect of cAMP on FMR1.1. Studies on the cell model of Fra(X):A methylation sensitive element (MSB) has been found in the CpG island of FMR1 promoter. Nitric oxide(NO) can induce an abnormal methylation on it through activation of DNA methyltransferase. Then FMR1 is silenced. According to this finding,a simple and steady cell model of Fra(X) was made through silencing the FMR1 of PBMC.2. Studies on the mechanism of intracellular cAMP reduction in Fra(X):Two groups of PBMC were studied. The experiment group was cultured with SNP to silence the FMR1 and the control group was cultured with SNP as well as L-NIL to depress the gene-silence effect. We found that the FMR1 was fully silenced in the former but wasn't in the latter. And the intracellular cAMP level in the former war lower,just as what it was in the Fra(X) patient. Spectrophotometry was used to measure the two key enzymes(AC and PDE),which determine the intracellular cAMP level,in the cAMP metabolism. As a result,the AC activity in the experiment group was significantly suppressed and no difference was found on PDE in the two groups. This finding indicates that the suppression of AC activity might be the reason of intracellular cAMP reduction.3. the gene-regulate effect of cAMP on FMR1:A cAMP-responsive element was found in the MSB of FMR1 promoter. The intracellular cAMP level of Fra(X) cell model was heightened by activation of AC and/or inhibition of PDE. An advanced FMR1 expression was found which might be valuable for the treatment of Fra(X).