Washington University in St. Louis

Research by Vitaly Klyachko, PhD, and colleagues has shed new light on brain dysfunctions associated with fragile X syndrome.

Congratulations to the Klyachko Lab!

In collaboration with colleagues at Emory University and WU’s departments of Biomedical Engineering and Anatomy/Neurobiology, Pan-Yue Deng and Vitaly Klyachko have just published a new paper in PNAS USA.

Myrick LK*, Deng PY*, Hashimoto H, Oh YM,  Cho Y, Poidevin MJ, Suhl JA, Visootsak J,   Cavalli V,  Jin P, Cheng X, Warren, ST*, and Klyachko, VA*.  (2015 )  Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures.”  PNAS USA, [E-published January 5]

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 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.

* To access the complete journal article, click here.

* * Click here to see the Washington University School of Medicine January 16, 2015 news release about these latest findings!

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