title: Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures.
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 interaction with the large-conductance calcium-activated 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.
authors.affiliation: Departments of Human Genetics.
authors.forename: Leila K
authors.initials: LK
authors.lastname: Myrick
authors.affiliation: Departments of Biomedical Engineering and Cell Biology and Physiology and.
authors.forename: Pan-Yue
authors.initials: PY
authors.lastname: Deng
authors.affiliation: Biochemistry, and.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Anatomy and Neurobiology, Washington University, St. Louis, MO 63110.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Oh
authors.affiliation: Anatomy and Neurobiology, Washington University, St. Louis, MO 63110.
authors.forename: Yongcheol
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Departments of Human Genetics.
authors.forename: Mickael J
authors.initials: MJ
authors.lastname: Poidevin
authors.affiliation: Departments of Human Genetics.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Suhl
authors.affiliation: Departments of Human Genetics, Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; and.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Visootsak
authors.affiliation: Anatomy and Neurobiology, Washington University, St. Louis, MO 63110.
authors.forename: Valeria
authors.initials: V
authors.lastname: Cavalli
authors.affiliation: Departments of Human Genetics.
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.affiliation: Biochemistry, and.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Departments of Human Genetics, Biochemistry, and Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; and swarren@emory.edu klyachko@wustl.edu.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Warren
authors.affiliation: Departments of Biomedical Engineering and Cell Biology and Physiology and swarren@emory.edu klyachko@wustl.edu.
authors.forename: Vitaly A
authors.initials: VA
authors.lastname: Klyachko
mesh_terms: D000200:Action Potentials / Q000235:genetics; D019943:Amino Acid Substitution; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004330:Drosophila; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D012640:Seizures / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse
keywords: BK channels; FMR1 sequencing; FMRP; fragile X syndrome; missense mutation