A novel fragile X syndrome mutation reveals a conserved role for the carboxy‐terminus in FMRP localization and function. Issue 4 (18th February 2015)

• Record Type: Journal Article
• Authors: Okray, Zeynep; de Esch, Celine EF; Van Esch, Hilde; Devriendt, Koen; Claeys, Annelies; Yan, Jiekun; Verbeeck, Jelle; Froyen, Guy; Willemsen, Rob; de Vrij, Femke MS; Hassan, Bassem A
• Is Part Of: EMBO molecular medicine. Volume 7:Issue 4(2015:Apr.)
• Page Start: 423
• Page End: 437
• Publication Date: 2015-02-18
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201404576
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201404576-abs-0001"> <title>Abstract</title> <p>Loss of function of the <italic>FMR1</italic> gene leads to fragile X syndrome (FXS), the most common form of intellectual disability. The loss of <italic>FMR1</italic> function is usually caused by epigenetic silencing of the <italic>FMR1</italic> 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 <italic>FMR1</italic> 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 <italic>FMR1</italic> locus. In one patient, we identified a guanine insertion in <italic>FMR1</italic> 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. <italic>In vivo</italic> analyses in <italic>Drosophila</italic> demonstrate that a patient‐mimetic mutation alters the localization and function of Dfmrp in neurons, leading to neomorphic neuronal phenotypes.</p> </abstract>