A novel fragile X syndrome mutation reveals a conserved role for the carboxy‐terminus in FMRP localization and function

Loss of function of the FMR 1 gene leads to fragile X syndrome ( FXS ), the most common form of intellectual disability. The loss of FMR 1 function is usually caused by epigenetic silencing of the FMR 1 promoter leading to expansion and subsequent methylation of a CGG repeat in the 5′ untranslated region. Very few coding sequence variations have been experimentally characterized and shown to be causal to the disease. Here, we describe a novel FMR 1 mutation and reveal an unexpected nuclear export function for the C‐terminus of FMRP . We screened a cohort of patients with typical FXS symptoms who tested negative for CGG repeat expansion in the FMR 1 locus. In one patient, we identified a guanine insertion in FMR 1 exon 15. This mutation alters the open reading frame creating a short novel C‐terminal sequence, followed by a stop codon. We find that this novel peptide encodes a functional nuclear localization signal ( NLS ) targeting the patient FMRP to the nucleolus in human cells. We also reveal an evolutionarily conserved nuclear export function associated with the endogenous C‐terminus of FMRP . In vivo analyses in Drosophila demonstrate that a patient‐mimetic mutation alters the localization and function of Dfmrp in neurons, leading to neomorphic neuronal phenotypes.