Evidence that fragile X mental retardation protein is a negative regulatorof translation

Fragile X syndrome is a common form of inherited mental retardation, Most f ragile X patients exhibit mutations in the fragile X mental retardation gen e 1 (FMR1) that lead to transcriptional silencing and hence to the absence of the fragile X mental retardation protein (FMRP), Since FMRP is an RNA-bi nding protein which associates with polyribosomes, it had been proposed to function as a regulator of gene expression at the post-transcriptional leve l. In the present study, we show that FMRP strongly inhibits translation of various mRNAs at nanomolar concentrations in both rabbit reticulocyte lysa te and microinjected Xenopus laevis oocytes, This effect is specific for FM RP, since other proteins with similar RNA-binding domains, including the au tosomal homologues of FMRP, FXR1 and FXR2, failed to suppress translation i n the same concentration range. Strikingly, a disease-causing lle-->Asn sub stitution at amino acid position 304 (I304N) renders FMRP incapable of inte rfering with translation in both test systems. Initial studies addressing t he underlying mechanism of inhibition suggest that FMRP inhibits the assemb ly of 80S ribosomes on the target mRNAs, The failure of FMRP I304N to suppr ess translation is not due to its reduced affinity for mRNA or its interact ing proteins FXR1 and FXR2, Instead, the I304N point mutation severely impa irs homo-oligomerization of FMRP, Our data support the notion that inhibiti on of translation may be a function of FMRP in vivo. We further suggest tha t the failure of FMRP to oligomerize, caused by the I304N mutation, may con tribute to the pathophysiological events leading to fragile X syndrome.