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.
journal_name
Proc Natl Acad Sci U S Aauthors
Myrick LK,Deng PY,Hashimoto H,Oh YM,Cho Y,Poidevin MJ,Suhl JA,Visootsak J,Cavalli V,Jin P,Cheng X,Warren ST,Klyachko VAdoi
10.1073/pnas.1423094112subject
Has Abstractpub_date
2015-01-27 00:00:00pages
949-56issue
4eissn
0027-8424issn
1091-6490pii
1423094112journal_volume
112pub_type
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