Fragile X syndrome is caused by loss of function of a single gene encoding the
Fragile X Mental Retardation Protein (FMRP). This
RNA-binding protein, widely expressed in mammalian tissues, is particularly abundant in neurons and is a component of
messenger ribonucleoprotein (
mRNP) complexes present within the translational apparatus. The absence of FMRP in neurons is believed to cause translation dysregulation and defects in
mRNA transport essential for local
protein synthesis and for synaptic development and maturation. A prevalent model posits that FMRP is a nucleocytoplasmic shuttling
protein that transports its
mRNA targets from the nucleus to the translation machinery. However, it is not known which of the multiple FMRP
isoforms, resulting from the numerous alternatively spliced FMR1 transcripts variants, would be involved in such a process. Using a new generation of anti-FMRP
antibodies and recombinant expression, we show here that the most commonly expressed human FMRP
isoforms (ISO1 and 7) do not localize to the nucleus. Instead, specific FMRP
isoforms 6 and 12 (ISO6 and 12), containing a novel C-terminal domain, were the only
isoforms that localized to the nuclei in cultured human cells. These
isoforms localized to specific
p80-coilin and SMN positive structures that were identified as Cajal bodies. The Cajal body localization signal was confined to
a 17 amino acid stretch in the C-terminus of human ISO6 and is lacking in a mouse Iso6 variant. As FMRP is an
RNA-binding protein, its presence in Cajal bodies suggests additional functions in nuclear post-transcriptional
RNA metabolism. Supporting this hypothesis, a missense mutation (I304N), known to alter the KH2-mediated
RNA binding properties of FMRP, abolishes the localization of human FMRP ISO6 to Cajal bodies. These findings open unexplored avenues in search for new insights into the pathophysiology of
Fragile X Syndrome.