Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome

Fragile X syndrome results from the absence of the RNA binding FMR protein. Here, mRNA was coimmunoprecipitated with the FMRP ribonucleoprotein comple x and used to interrogate microarrays. We identified 432 associated mRNAs f rom mouse brain. Quantitative RT-PCR confirmed some to be >60-fold enriched in the immunoprecipitant. In parallel studies, mRNAs from polyribosomes of fragile X cells were used to probe microarrays. Despite equivalent cytopla smic abundance, 251 mRNAs had an abnormal polyribosome profile in the absen ce of FMRP. Although this represents <2% of the total messages, 50% of the coimmunoprecipitated mRNAs with expressed human orthologs were found in thi s group. Nearly 70% of those transcripts found in both studies contain a G quartet structure, demonstrated as an in vitro FMRP target. We conclude tha t translational dysregulation of rnRNAs normally associated with FMRP may b e the proximal cause of fragile X syndrome, and we identify candidate genes relevant to this phenotype.