Study of the serotonin transporter (SLC6A4) and BDNF genes in French patients with non syndromic mental deficiency

<p>Abstract</p> <p>Background</p> <p>Mental deficiency has been linked to abnormalities in cortical neuronal network connectivity and plasticity. These mechanisms are in part under the control of two interacting signalling pathways, the serotonergic and the brain-derived neurotrophic (BDNF) pathways. The aim of the current paper is to determine whether particular alleles or genotypes of two crucial genes of these systems, the serotonin transporter gene (<it>SLC6A4</it>) and the brain-derived neurotrophic factor gene (<it>BDNF</it>), are associated with mental deficiency (MD).</p> <p>Methods</p> <p>We analyzed four functional polymorphisms (rs25531, 5-HTTLPR, VNTR, rs3813034) of the <it>SLC6A4 </it>gene and one functional polymorphism (Val66 Met) of the <it>BDNF </it>gene in 98 patients with non-syndromic mental deficiency (NS-MD) and in an ethnically matched control population of 251 individuals.</p> <p>Results</p> <p>We found no significant differences in allele and genotype frequencies in the five polymorphisms studied in the <it>SLC6A4 </it>and <it>BDNF </it>genes of NS-MD patients versus control patients. While the comparison of the patterns of linkage disequilibrium (D') in the control and NS-MD populations revealed a degree of variability it did not, however, reach significance. No significant differences in frequencies of haplotypes and genotypes for VNTR/rs3813034 and rs25531/5-HTTLPR were observed.</p> <p>Conclusion</p> <p>Altogether, results from the present study do not support a role for any of the five functional polymorphisms of <it>SLC6A4 </it>and <it>BDNF </it>genes in the aetiology of NS-RM. Moreover, they suggest no epistatic interaction in NS-MD between polymorphisms in <it>BDNF </it>and <it>SLC6A4</it>. However, we suggest that further studies on these two pathways in NS-MD remain necessary.</p

Transcriptional Silencing of the TFPI-2 Gene by Promoter Hypermethylation in Choriocarcinoma Cells

International audienceTissue factor pathway inhibitor-2 (TFPI-2), a Kunitztype serine proteinase inhibitor associated with the extracellular matrix, has been shown to reduce tumor invasion. In the present study we identified the presence of a complete CpG island region spanning exon 1 and the three transcription initiation sites. We demonstrate that DNA demethylation by 5'-aza-2'-deoxycytidine restores TFPI-2 transcription in JAR choriocarcinoma cells. The effect of in vitro DNA methylation on TFPI-2 promoter function was also confirmed with TFPI-2/luciferase promoter constructs. Finally, we determined the precise methylation status of CpG sites of the TFPI-2 promoter in normal and tumor trophoblast cells using the bisulfite genomic sequencing method. We conclude that hypermethylation of the TFPI-2 gene is correlated with transcriptional silencing and that the TFPI-2 gene may be a candidate tumor suppressor gene