INT255112

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Context Info
Confidence 0.58
First Reported 2008
Last Reported 2010
Negated 0
Speculated 0
Reported most in Body
Documents 22
Total Number 26
Disease Relevance 8.50
Pain Relevance 0.45

This is a graph with borders and nodes. Maybe there is an Imagemap used so the nodes may be linking to some Pages.

mRNA processing (Mbnl1) RNA binding (Mbnl1) nucleus (Mbnl1)
cytoplasm (Mbnl1)
Anatomy Link Frequency
heart 3
skeletal muscle 2
cardiac muscle 1
myoblasts 1
neurons 1
Mbnl1 (Mus musculus)
Pain Link Frequency Relevance Heat
gABA 63 93.68 High High
GABAergic 70 92.24 High High
anesthesia 33 87.20 High High
imagery 70 83.28 Quite High
Kinase C 2 53.12 Quite High
interneuron 7 21.12 Low Low
tolerance 40 5.00 Very Low Very Low Very Low
fibrosis 13 5.00 Very Low Very Low Very Low
cytokine 10 5.00 Very Low Very Low Very Low
Central nervous system 10 5.00 Very Low Very Low Very Low
Disease Link Frequency Relevance Heat
Frailty 224 98.78 Very High Very High Very High
Targeted Disruption 477 98.40 Very High Very High Very High
Toxicity 212 98.16 Very High Very High Very High
Disease 194 97.64 Very High Very High Very High
Hypopituitarism 38 97.64 Very High Very High Very High
Muscle Disease 28 96.96 Very High Very High Very High
Cognitive Disorder 27 94.48 High High
Myotonia 70 92.16 High High
Congenital Anomalies 172 90.48 High High
Cataract 52 89.52 High High

Sentences Mentioned In

Key: Protein Mutation Event Anatomy Negation Speculation Pain term Disease term
We show that overexpression of CUGBP1 in human SK-N-SH cells, or depletion of MBNL1, result in an upregulation of GABT4 that mimics the in vivo changes in steady state levels caused by CUGexp transcripts.
Negative_regulation (depletion) of MBNL1 in SK-N-SH
1) Confidence 0.58 Published 2009 Journal PLoS Genetics Section Body Doc Link PMC2719092 Disease Relevance 0.08 Pain Relevance 0.08
Specifically, disruption of Mbnl1 in mice is sufficient to recapitulate key features of the disease [32].
Negative_regulation (disruption) of Mbnl1 associated with disease
2) Confidence 0.55 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0.33 Pain Relevance 0
Here, we present three lines of evidence that RNA gain-of-function plays a significant role in SCA8: 1) CUGexp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons in the brain; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUGexp transcripts trigger splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4).
Negative_regulation (loss) of Mbnl1 in brain associated with gaba
3) Confidence 0.43 Published 2009 Journal PLoS Genetics Section Abstract Doc Link PMC2719092 Disease Relevance 0.23 Pain Relevance 0.13
To test if genetic Mbnl1 loss enhances the SCA8 CNS phenotype we crossed heterozygous SCA8 BAC-EXP5+/?
Negative_regulation (loss) of Mbnl1
4) Confidence 0.43 Published 2009 Journal PLoS Genetics Section Body Doc Link PMC2719092 Disease Relevance 0.63 Pain Relevance 0
We present three lines of evidence that CUGexp transcripts play a significant role in SCA8: 1) CUGexp transcripts accumulate as ribonuclear inclusions that co-localize with MBNL1 in selected neurons; 2) loss of Mbnl1 enhances motor deficits in SCA8 mice; 3) SCA8 CUGexp transcripts trigger alternative splicing changes and increased expression of the CUGBP1-MBNL1 regulated CNS target, GABA-A transporter 4 (GAT4/Gabt4) which is associated with the predicted loss of GABAergic inhibition within the granular cell layer in SCA8 mice.
Negative_regulation (loss) of Mbnl1 in neurons associated with gaba and gabaergic
5) Confidence 0.43 Published 2009 Journal PLoS Genetics Section Abstract Doc Link PMC2719092 Disease Relevance 0.38 Pain Relevance 0.09
First, we demonstrate that SCA8 CUGexp transcripts form hallmark ribonuclear inclusions that co-localize with MBNL1 in humans and mice and that genetic loss of Mbnl1 enhances motor coordination deficits in SCA8 BAC-EXP mice.
Negative_regulation (loss) of Mbnl1
6) Confidence 0.43 Published 2009 Journal PLoS Genetics Section Body Doc Link PMC2719092 Disease Relevance 0.30 Pain Relevance 0.04
Taken together, these data suggest that expression of CUGexp or CCUGexp transcripts induces alternative splicing changes in DM skeletal and cardiac muscle by sequestration and functional loss of MBNL1 protein.
Negative_regulation (loss) of MBNL1 protein in cardiac muscle associated with frailty
7) Confidence 0.42 Published 2009 Journal PLoS Genetics Section Body Doc Link PMC2719092 Disease Relevance 0.96 Pain Relevance 0
50% decrease in Mbnl1 is insufficient to alter splice site choice [32], these data demonstrate that aggregation per se cannot be the sole mechanism that underlies MBNL1 inactivation in DM1 cells.
Negative_regulation (inactivation) of MBNL1
8) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0 Pain Relevance 0
Specifically, we have shown that siRNA mediated inactivation of MBNL1, which binds to the stem of the CUG hairpin, results in increased dispersion of nuclear foci in DM1 cells [46]. siRNA mediated reduction of hnRNP H, which binds to the base of the CUG hairpin, has also been demonstrated to allow transport of RNAs encoding expanded CUG repeats into the cytoplasm [51].
Negative_regulation (inactivation) of MBNL1 in stem
9) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0 Pain Relevance 0
These results demonstrate that (i) CTG tracts expressed in a context independent manner can elicit elevated Cug-bp1 levels, (ii) a two fold elevation of Cug-bp1 levels is insufficient to dysregulate splice site choice in the adult mouse heart and (iii) aggregation of Mbnl1 in CUG foci per se may not be sufficient to inactivate Mbnl1.
Negative_regulation (inactivate) of Mbnl1 in heart
10) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0.25 Pain Relevance 0.09
These data therefore demonstrate first, that functional inactivation of MBNL1 is sufficient to produce DM1 pathophysiology.
Negative_regulation (inactivation) of MBNL1
11) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0.34 Pain Relevance 0
As previous studies have shown marked sequestration of MBNL1 in CUG foci both in skeletal muscle and heart cells (35,36), it has been hypothesized that MBNL1 depletion occurring as a consequence of aberrant sequestration, is a key mechanism that underlies the functional inactivation of MBNL1 in DM1.
Negative_regulation (inactivation) of MBNL1 in heart
12) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0.21 Pain Relevance 0
Second, as MBNL1 mediated rescue serves to correct key features of DM1, inactivation of MBNL1 must be a necessary event that is required for the development of DM1 pathophysiology.
Negative_regulation (inactivation) of MBNL1
13) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0.32 Pain Relevance 0
The molecular basis of MBNL1 inactivation in DM1 myoblasts is currently unclear and is an important area of future investigation.
Negative_regulation (inactivation) of MBNL1 in myoblasts
14) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0 Pain Relevance 0
Inactivation of MBNL1 plays an important role in etiology of DM1 spliceopathy.
Negative_regulation (Inactivation) of MBNL1
15) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0.31 Pain Relevance 0
As previous studies have shown marked sequestration of MBNL1 in CUG foci both in skeletal muscle and heart cells (35,36), it has been hypothesized that MBNL1 depletion occurring as a consequence of aberrant sequestration, is a key mechanism that underlies the functional inactivation of MBNL1 in DM1.
Negative_regulation (depletion) of MBNL1 in heart
16) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0.22 Pain Relevance 0
50% decrease in Mbnl1 is insufficient to alter splice site choice [32], these data demonstrate that aggregation per se cannot be the sole mechanism that underlies MBNL1 inactivation in DM1 cells.
Negative_regulation (decrease) of Mbnl1
17) Confidence 0.40 Published 2008 Journal PLoS ONE Section Body Doc Link PMC2597774 Disease Relevance 0.05 Pain Relevance 0
Because co-localization of MBNL1 with CUGexp ribonuclear inclusions is thought to lead to functional impairment of nuclear MBNL1 activity in DM1, we tested the hypothesis that RNA gain-of-function effects in SCA8 contribute to the motor deficits in SCA8 BAC-EXP mice via Mbnl1 depletion.
Negative_regulation (depletion) of Mbnl1
18) Confidence 0.37 Published 2009 Journal PLoS Genetics Section Body Doc Link PMC2719092 Disease Relevance 0.41 Pain Relevance 0
The nuclear CUGn aggregates sequester MBNL1 (Muscleblind) protein [31,54], causing local reduction of MBNL1.
Negative_regulation (reduction) of MBNL1
19) Confidence 0.35 Published 2010 Journal Current Genomics Section Body Doc Link PMC2874224 Disease Relevance 0.71 Pain Relevance 0
Based on these results, it is reasonable to suggest that DM1 phenotype could be caused equally well by the reduction of MBNL1 and by the increase of CUGBP1.
Negative_regulation (reduction) of MBNL1
20) Confidence 0.35 Published 2010 Journal Current Genomics Section Body Doc Link PMC2874224 Disease Relevance 0.48 Pain Relevance 0

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