Presentation on theme: "The FMR1 disorders (Fragile X syndrome, etc). Mary Beth Busby founding board member of the Fragile X Research Foundation (FRAXA) Walter Kaufmann Director,"— Presentation transcript:
Mary Beth Busby founding board member of the Fragile X Research Foundation (FRAXA) Walter Kaufmann Director, Center for Genetic Disorders of Cognition and Behavior, Kennedy Krieger Institute, The Johns Hopkins UniversityCenter for Genetic Disorders of Cognition and Behavior Karen Usdin Chief, Gene Structure and Disease Section LMCB, NIDDK
Understanding the molecular basis of the FMR1 gene disorders Karen Usdin 5’ UTR exon 1 intron 1 (CGG)n promoter X chromosome
Premutation symptoms result from RNA “toxicity” The RNA is somehow deleterious the CGG-repeats may trigger deleterious processes sequester proteins that are important for normal neuronal and ovarian function
RNA “toxicity” hypothesis The RNA is somehow deleterious the CGG-repeats may initiate or trigger deleterious processes the CGG-repeats may sequester proteins that are important for normal neuronal and ovarian function
Take home messages FXTAS and FXPOI result from repeat-induced hyperexpression of the FMR1 gene and the deleterious effects of high levels of CGG-repeat containing mRNA. FXS results from repeat-induced gene silencing. silencing leads to a deficiency of FMRP, a protein important for the regulation of translation in the synapses of neurons the resultant abnormal expression of proteins like mGluR5, GSK-3, GABA A and MMP-9 results in the symptoms of FXS normalizing expression of these proteins may provide targeted approaches to the treatment of FXS.