Journal Article

Independent role for presynaptic FMRP revealed by anFMR1missense mutation associated with intellectual disability and seizures

Klyachko, Vitaly A., Visootsak, Jeannie, Deng, Pan-Yue, Poidevin, Mickael J., Cheng, Xiaodong, Hashimoto, Hideharu, Cavalli, Valeria, Oh, Young Mi, Myrick, Leila K., Cho, Yongcheol, Suhl, Joshua A., Jin, Peng, Warren, Stephen T.

2015

Overview

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 anFMR1missense 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)-deficientDrosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening inFmr1KO 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.

• Publisher: National Academy of Sciences
• Subject: INAUGURAL ARTICLES