Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

• Type of Material: Article
• Authors: Leila K. Myrick, Emory University; Pan-Yue Deng, Washington University; Hideharu Hashimoto, Emory University; Young Mi Oh, Washington University; Yongcheol Cho, Washington University; Mickael J. Poidevin, Emory University; Joshua A. Suhl, Emory University; Jeannie Visootsak, Emory University; Valeria Cavalli, Washington University; Peng Jin, Emory University; Xiaodong Cheng, Emory University; Stephen Warren, Emory University; Vitaly A. Klyachko, Washington University
• Language: English
• Date: 2015-01-27
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2015 National Academy of Sciences
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1423094112
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 112
• Issue: 4
• Start Page: 949
• End Page: 956
• Grant/Funding Information: This work was supported, in part, by NIH Award NS091859 from the National Institute of Neurological Disorders and Stroke and the Eunice Kennedy Shriver National Institute of Child Health and Human Development in support of the Emory National Fragile X Research Center (to S.T.W.) and by NIH Grant R01 NS089449 and a FRAXA Foundation grant (both to V.A.K.). H.H. and X.C. were supported by NIH Grant R01 GM049245-21.
• Keywords: SYNAPTIC STRUCTURE; NEURONAL EXCITABILITY; MOUSE MODEL; Science & Technology - Other Topics; METABOTROPIC GLUTAMATE RECEPTORS; DEPENDENT TRANSLATION; DENTATE GYRUS; FMRP; missense mutation; PROTEIN-SYNTHESIS; POTASSIUM CHANNELS; FMR1sequencing; Science & Technology; fragile X syndrome; BK channels; BK CHANNELS; X MENTAL-RETARDATION; Multidisciplinary Sciences
• Research Categories: Chemistry, Biochemistry; Biology, Genetics

Abstract

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interactionwith the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.