title: A novel fragile X syndrome mutation reveals a conserved role for the carboxy-terminus in FMRP localization and function.
abstract: Loss of function of the FMR1 gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of FMR1 function is usually caused by epigenetic silencing of the FMR1 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 FMR1 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 FMR1 locus. In one patient, we identified a guanine insertion in FMR1 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.
authors.affiliation: VIB Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium Program in Molecular and Developmental Genetics, Doctoral School of Biomedical Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Okray
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Celine E F
authors.initials: CE
authors.lastname: de Esch
authors.affiliation: Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: VIB Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Claeys
authors.affiliation: VIB Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Jiekun
authors.initials: J
authors.lastname: Yan
authors.affiliation: VIB Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Jelle
authors.initials: J
authors.lastname: Verbeeck
authors.affiliation: VIB Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.affiliation: Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Femke M S
authors.initials: FM
authors.lastname: de Vrij
authors.affiliation: VIB Center for the Biology of Disease, VIB, Leuven, Belgium Center for Human Genetics, University of Leuven School of Medicine and University Hospitals Leuven, Leuven, Belgium Program in Molecular and Developmental Genetics, Doctoral School of Biomedical Sciences, University of Leuven, Leuven, Belgium bh@kuleuven.be.
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Hassan
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004331:Drosophila melanogaster; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000235:genetics; D019680:Trinucleotide Repeat Expansion
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D019913:Nuclear Localization Signals; C497683:FMR1 protein, human
keywords: Drosophila; axon guidance; fragile X syndrome; nuclear export; nucleolus