A Mouse Model of the Human Fragile X Syndrome I304N Mutation

Zang, Julie B.; Nosyreva, E. D.; Spencer, Corinne M.; Volk, Lenora J.; Musunuru, Kiran; Zhong, Ruiqin; Stone, Elizabeth F.; Yuva-Paylor, Lisa A.; Huber, Kimberly M.; Paylor, Richard; Darnell, Robert B.

doi:10.1371/journal.pgen.1000758

Cited by 118 publications

(134 citation statements)

References 87 publications

(130 reference statements)

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“…Both of these mutations reside within the RNA binding domains of FMRP and result in loss of RNA binding and polyribosome association (26,28). Studies of these mutations provide strong evidence that FMRP's inability to regulate protein synthesis is a critical component of FXS pathophysiology, given that both of the patients with the G266E and I304N mutations presented with a very characteristic FXS phenotype, including marked ID, developmental delay, macroorchidism, and dysmorphic facies.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

131

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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 calciumactivated 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.F ragile X syndrome (FXS) is the most common single-gene disorder responsible for intellectual disability (ID) in patients (1). Along with cognitive dysfunction, the syndrome typically presents with several other comorbidities, including behavioral and social impairments (anxiety and autism spectrum disorder), neurological defects (seizures and abnormal sleep patterns), and morphological abnormalities (dysmorphic facies and macroorchidism). Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP.FMRP has complex multifaceted functions at synapses both in pre-and postsynaptic compartments. As an RNA binding protein, FMRP is best known for its function as a translation regulator in dendrites (2). Loss of FMRP has been linked to various forms of long-term synaptic plasticity defects that depend on local protein synthesis in the postsynaptic neuron (3). In addition to disrupted metabotropic glutamate receptor signaling, which has been shown across multiple brain regions (4-7), FMRP is necessary for activitydependent protein synthesis downstream of other signaling receptor pathways, including ACh, dopamine, and TrkB (8-10).Although postsynaptic control of translation is believed to be the dominant function of FMRP, it is unable to explain all of the pathophysiology observed in FXS animal models. For instance, in Drosophila, presynaptic expression of the FMR1 homolog, dfmr1, completely rescues the synaptic overgrowth phenotype at the neuromuscular junction (NMJ) in dfmr1-null mutants (11-13). In rodent brain, FMRP has been found in structures called fragile-X granules, which are ...

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Section: Discussionmentioning

confidence: 99%

“…However, to date, only two missense mutations have been reported to cause FXS, and both mutations result in functional null forms of FMRP that phenocopy transcriptionally silenced repeat expansion mutations (26)(27)(28).…”

mentioning

confidence: 99%

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

131

View full text Add to dashboard Cite

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“…FMRP contains three canonical RNA binding domains, two ribonucleoprotein K homology domains (KH1, KH2), and an arginine-glycine-glycine repeat-containing RGG box. An isoleucine 304 to asparagine missense mutation (Ile304Asn) in the KH2 domain, associated with severe clinical symptoms of FXS, has been shown to behave like a null mutation with reduced RNA binding and polyribosome association in a mouse model [41]. More recently, a patient diagnosed with FXS was found to have a glycine 266 to glutamic acid (Gly266Glu) missense mutation in the KH1 domain, which also disrupted RNA binding and polyribosome association [42].…”

Section: Molecular Functions Of Fmrp: Targets and Molecular Mechanismmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

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Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

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“…1,2 The RNA binding protein, Fragile-X-Mental-Retardation-syndrome-Related protein 1 (FXR1) [3][4][5] is overexpressed and associated with poor clinical outcomes in multiple cancers. 6 FXR1 is similar to Fragile-X-Mental Retardation Protein 1 (FMR1), 4,[7][8][9][10][11][12][13][14] and is implicated at multiple levels of post-transcriptional control, including translation, mRNA stability and transport. 7-10, 12-13, 15-18 FXR1 is associated with negative regulation of specific growth factor and cytokine mRNAs in myocytes 5,[19][20][21][22] and macrophages, 16 which can control development, cell differentiation and cell state specific functions.…”

Section: Introductionmentioning

confidence: 99%

Regulation of monocyte induced cell migration by the RNA binding protein, FXR1

et al. 2016

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FXR1 belongs to a family of RNA-binding proteins that play critical roles in post-transcriptional regulation of gene expression in immunity, development and cancer. FXR1 is associated with regulation of specific mRNAs in myocytes and macrophages. In quiescent cells (> 24 h of extended serum-starvation, »30-48 h or more), a spliced isoform of FXR1, FXR1a, promotes translation of the cytokine TNFa, independent of the effects of RNA levels. Here we examined the role of FXR1 in THP1 human monocytic leukemic cells that were grown in serum, as well as in early (24 h) serum-starvation conditions that demonstrates differences in gene expression mechanisms and is distinct from quiescent (> 24 h extended serum-starvation) cells. Global RNA profiling, conducted to investigate the role of FXR1 on mRNA levels, revealed that FXR1 affects levels of specific mRNAs in serum-grown and in early 24 h serum-starvation conditions. FXR1 decreases levels of several mRNAs, including as previously identified, CDKN1A (p21CIP1 or p21) mRNA in serumgrown cells. Interestingly, we find that FXR1 positively regulates mRNA levels of specific cytokines and chemokines in serum-grown and in early 24 h serum-starvation conditions. These include IL1b and CCL2 that control cell migration. Accordingly, depletion and overexpression of FXR1 decreased and increased levels of CCL2 mRNA. Consistent with the reduced levels of IL1b, CCL2 and other chemokines upon FXR1 depletion, our data reveal that depletion of FXR1 decreases the ability of these cells to induce cell migration of neighboring monocytic cells. These data reveal a new role of FXR1 in controlling induction of monocyte migration.

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A Mouse Model of the Human Fragile X Syndrome I304N Mutation

Cited by 118 publications

References 87 publications

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Regulation of monocyte induced cell migration by the RNA binding protein, FXR1

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