Fragile X syndrome (FXS) is an X-linked condition associated with intellectual disability and behavioral problems. It is caused by expansion of a CGG repeat in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene. This mutation is associated with hypermethylation at the FMR1 promoter and resultant transcriptional silencing. FMR1 silencing has many consequences, including up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. mGluR5 receptor antagonists have shown promise in preclinical FXS models and in one small open-label study of FXS. We examined whether a receptor subtype-selective inhibitor of mGluR5, AFQ056, improves the behavioral symptoms of FXS in a randomized, double-blind, two-treatment, two-period, crossover study of 30 male FXS patients aged 18 to 35 years. We detected no significant effects of treatment on the primary outcome measure, the Aberrant Behavior Checklist-Community Edition (ABC-C) score, at day 19 or 20 of treatment. In an exploratory analysis, however, seven patients with full FMR1 promoter methylation and no detectable FMR1 messenger RNA improved, as measured with the ABC-C, significantly more after AFQ056 treatment than with placebo (P < 0.001). We detected no response in 18 patients with partial promotermethylation. Twenty-four patients experienced an adverse event, which was mostly mild to moderately severe fatigue or headache. If confirmed in larger and longer-term studies, these results suggest that blockade of the mGluR5 receptor in patients with full methylation at the FMR1 promoter may show improvement in the behavioral attributes of FXS.

Reference EPFL-CONF-178514View record in Web of Science Record created on 2012-06-25, modified on 2016-08-09

promoter. FMR1 accomplished routinely, at least in patients in which the silence within lies in the may be −− believed to underlie many of the characteristic behaviors associated with fragile X −− glutamate system response in a population of patients with fragile X syndrome. It also offers hope that inhibition of the metabotropic for a larger study, appropriately designed to test whether methylation can serve as a predictor of a positive antagonist promoter provides the basis FMR1 This correlation between response to treatment and methylation status of the patient group with partially methylated promoters showed no such changes. primary behavioral measures, exhibiting a boost in performance 19 or 20 days after treatment was started. The promoters showed improvement by the FMR1 member of the subgroup of patients who harbored fully methylated subjects who were given a placebo treatment. In a subsequent exploratory analysis, the authors found that each differences observed in a secondary collection of tests, when the drug-treated patient group was compared with no effect on the behaviors measured by these primary tests, but administration of the drug did correlate with had to detect stereotypic behavior, hyperactivity, and inappropriate speech. In this clinical trial, the mGluR5 antagonist promoter, as well as running a large battery of behavioral tests designed FMR1 assayed the methylation status of the pattern. So when the authors tested the effects of a newly described mGluR5 inhibitor on fragile X patients, they there is a broad variation among patients in the structure of the gene and its methylation −− generation to generation and even from −− impaired transcription. Because the number of triplet repeats differs widely from person to person of the triplet base pairs CGG, a distortion that is accompanied by extra methylation at the gene's promoter and thus gene can contain as many as several thousand extra repeats FMR1 In individuals with fragile X syndrome, the that defines fragile X patients who could benefit from treatment with mGluR5 antagonists. methylated, a sign that gene expression is completely silenced. This molecular aberration might serve as a signature gene in drug-responsive patients is fully FMR1 but an analysis of those who did revealed that the promoter of the have now treated a group of 30 fragile X patients with such an antagonist. Not all subjects showed improvement, al. et signaling and behavioral problems, administration of an mGluR5 antagonist improves the symptoms. Jacquemont But in mice and fruit flies that carry the same genetic defects as patients and also show enhanced glutamate receptor in patients during childhood, and currently these symptoms are treatable only with supportive behavioral measures. mGluR5. This noisy signaling pathway contributes to the cognitive deficits and differences that first become apparent myriad molecular changes, most notably a turning up of signaling through the metabotropic glutamate receptor ) silences its expression, which gives rise to FMR1 gene ( fragile X mental retardation 1 this disorder, a defect in the the silence within. But for patients suffering from fragile X syndrome, it is the silence within that turns up the noise. In Through the practice of meditation, students of Eastern philosophies are taught to turn down the noise to find A Methylation Marker for Fragile X Syndrome

La presente invention concerne un procede permettant de determiner l'issue therapeutique d'un traitement impliquant un agent therapeutique efficace contre la DMLA chez un patient souffrant de DMLA. Ce procede comprend les etapes consistant a prelever un echantillon sur le patient et a analyser l'echantillon a la recherche d'un ou plusieurs biomarqueurs associes a une reponse amelioree au traitement impliquant ledit agent therapeutique efficace contre la DMLA.

Charles Paulding and colleagues report a genome-wide association study for susceptibility to lumiracoxib-induced liver injury. The study utilized lumiracoxib-treated cases with liver injury and lumiracoxib-treated controls, and included independent replication. The authors identify an association to a common HLA haplotype.

Gene duplication and domain accretion are thought to be the major mechanisms for the emergence of novel genes during evolution. Such events are thought to have occurred at early stages in the vertebrate lineage, but genomic sequencing has recently revealed extensive amplification events during the evolution of higher primates. We report here that the Tre2 (USP6) oncogene is derived from the chimeric fusion of two genes, USP32 (NY-REN-60), and TBC1D3. USP32 is an ancient, highly conserved gene, whereas TBC1D3 is derived from a recent segmental duplication, which is absent in most other mammals and shows rapid amplification and dispersal through the primate lineage. Remarkably, the chimeric gene Tre2 exists only in the hominoid lineage of primates. This hominoid-specific oncogene arose as recently as 21-33 million years ago, after proliferation of the TBC1D3 segmental duplication in the primate lineage. In contrast to the broad expression pattern of USP32 and TBC1D3, expression of Tre2 is testis-specific, a pattern proposed for novel genes implicated in the emergence of reproductive barriers. The sudden emergence of chimeric proteins, such as that encoded by Tre2, may have contributed to hominoid speciation.