期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：4
页码：949-956
DOI：10.1073/pnas.1423094112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAlthough loss of fragile X mental retardation protein 1 (FMRP) causes a wide range of abnormalities in both pre- and postsynaptic compartments, the link between various FMRP functions and specific phenotypes in patients has been difficult to establish. Through the study of a novel fragile X mental retardation 1 (FMR1) missense mutation, c.413G > A (R138Q), recently identified in a patient with a partial fragile X syndrome (FXS) phenotype (intellectual disability and seizures), we found that pre- and postsynaptic functions of FMRP are independent. Our findings suggest that loss of a presynaptic, translation-independent function of FMRP is linked with a specific subset of FXS clinical features. Our study thus provides a major step in teasing out the domain-specific functions of FMRP in pre- and postsynaptic compartments, and their contribution to various elements of FXS pathophysiology. 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.
关键词：fragile X syndrome ; missense mutation ; FMR1 sequencing ; FMRP ; BK channels
