Hyper-activation of nonsense-mediated mRNA decay in fragile X mental retardation syndrome

"Fragile X mental retardation syndrome (FXS) is the most common single-gene cause of inherited intellectual disability, and it is highly associated with autism spectrum disorder. The disease is the result of abnormally large expansions in the fragile X mental retardation gene that silence gene expression. When silenced, cells fail to produce a protein called fragile X mental retardation protein, or FMRP. FMRP is critical for our neurons to function properly. At the molecular level, FMRP represses the production of other proteins that mediate neuronal maturation and synaptic plasticity either directly or indirectly. We have serendipitously found that a cellular RNA destruction mechanism studied in our laboratory, called nonsense-mediated mRNA decay (NMD), is hyperactive in FXS, providing new insight into the cause of this disease. There are already drugs on the market that have been shown to inhibit NMD and that we propose can be repurposed for this outcome. One goal is to determine the cellular mechanism by which the efficiency of NMD is increased in FXS. Another goal is to obtain a comprehensive understanding of gene expression in brain cells considering that FXS is a neurologic disorder. "