FMRP ASSOCIATES WITH POLYRIBOSOMES AS AN MRNP, AND THE I304N MUTATIONOF SEVERE FRAGILE-X-SYNDROME ABOLISHES THIS ASSOCIATION

Fragile X mental retardation is caused by the lack of FMRP, a selectiv e RNA-binding protein associated with ribosomes. A missense mutation, I304N, has been found to result in an unusually severe phenotype. We s how here that normal FMRP associates with elongating polyribosomes via large mRNP particles. Despite normal expression and cytoplasmic mRNA association, the I304N FMRP is incorporated into abnormal mRNP particl es that are not associated with polyribosomes. These data indicate tha t association of FMRP with polyribosomes must be functionally importan t and imply that the mechanism of the severe phenotype in the I304N pa tient lies in the sequestration of bound mRNAs in nontranslatable mRNP particles. In the absence of FMRP, these same mRNAs may be partially translated via alternative mRNPs, although perhaps abnormally localize d or regulated, resulting in typical fragile X syndrome.