INT335731

Context Info Confidence 0.73 First Reported 2010 Last Reported 2010 Negated 0 Speculated 0 Reported most in Body Documents 1 Total Number 16 Disease Relevance 12.21 Pain Relevance 0.18

lipid binding (Vcp) cytosol (Vcp) transport (Vcp) endoplasmic reticulum (Vcp) ATPase activity (Vcp) nucleus (Vcp)

Anatomy Link Frequency muscle 4 quadriceps 1 embryos 1 liver 1 brain 1 Vcp (Mus musculus) Vcp - R155H (3)

Pain Link Frequency Relevance Heat Hippocampus 64 99.84 Neurotransmitter 16 66.96 imagery 48 58.80 Eae 80 42.60 cytokine 32 5.00 anesthesia 16 5.00 isoflurane 16 5.00 Pain 16 5.00

Disease Link Frequency Relevance Heat Apoptosis 384 100.00 Death 16 100.00 Disease 432 99.96 Targeted Disruption 1520 99.88 Embryonic Lethality 16 99.00 Muscle Weakness 272 98.86 Convulsion 208 98.12 Muscle Disease 160 94.00 Congenital Anomalies 64 92.56 Injury 32 91.76

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

Since seizures are not reported in human IBMPFD patients, these findings combined with the observation that VCP is abundantly expressed in hippocampus [60] propose an important role for VCP in the hippocampal region.

Gene_expression (expressed) of VCP in hippocampus associated with convulsion and hippocampus

1) Confidence 0.73 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 1.59 Pain Relevance 0.15

Additionally, Custer et al. have generated transgenic mice expressing VCP/p97 with the R155H and A232E mutations shown to develop pathology of the muscle, bone, and brain exhitibing similar characteristics seen in humans with IBMPFD [32].

Gene_expression (expressing) of VCP in muscle associated with targeted disruption

2) Confidence 0.73 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.87 Pain Relevance 0

The finding that inhibition of VCP expression promotes apoptosis [44] suggests that intact VCP is indispensable for normal development and cell survival.

Gene_expression (expression) of VCP associated with apoptosis

3) Confidence 0.73 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.98 Pain Relevance 0

We decided to generate a knock-in model, since these mice express the mouse VCP gene at endogenous level and are therefore believed to represent a better model to study the pathology of the human disease and to develop targeted molecular treatment.

Gene_expression (express) of VCP gene associated with targeted disruption and disease

4) Confidence 0.73 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.86 Pain Relevance 0

Targeted homozygous deletion of VCP by Cre-loxP technology was reported to result in early embryonic lethality [30] suggesting an important role for the intact VCP expression in the development of mouse embryos.

Gene_expression (expression) of VCP in embryos associated with embryonic lethality

5) Confidence 0.73 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.38 Pain Relevance 0

To be able to elucidate tissue and cellular pathology of IBMPFD, we have generated a knock-in mouse model that expresses the most common VCP disease mutation R155H at endogenous level.

Gene_expression (expresses) of VCP associated with targeted disruption and disease

6) Confidence 0.63 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.98 Pain Relevance 0

Our mice express the R155H mutant VCP gene at an endogenous level compared to previous models which overexpresses the mutant allele.

Gene_expression (express) of R155H mutant VCP gene (R155H)

7) Confidence 0.63 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 1.18 Pain Relevance 0.03

Progressive deterioration of muscle strength of knock-in mice mirrors the development of late onset muscle weakness reported in patients [1], [3], [45] and transgenic mice expressing R155H VCP [31].

Gene_expression (expressing) of R155H VCP (R155H) in muscle associated with targeted disruption and muscle weakness

8) Confidence 0.63 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 1.04 Pain Relevance 0

Transgenic mice overexpressing R155H VCP under a muscle-specific promoter, reported by Weihl et al (2006) [31], demonstrated muscle weakness, and slit-like vacuoles.

Gene_expression (overexpressing) of R155H VCP (R155H) in muscle associated with targeted disruption and muscle weakness

9) Confidence 0.63 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.87 Pain Relevance 0

Mutations in the VCP gene have been shown to trigger cell death with apoptotic features, whereas expression of wild-type protein has been suggested to have an anti-apoptotic effect [34], [35], [36].

Gene_expression (expression) of VCP gene associated with apoptosis and death

10) Confidence 0.63 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.92 Pain Relevance 0

VCP expression by Q-RT-PCR analyses demonstrated no statistically significant differences between wild type (AVG ?

Gene_expression (expression) of VCP

11) Confidence 0.56 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.34 Pain Relevance 0

These findings suggested that mutated VCP may also cause apoptosis in mouse muscle expressing the R155H disease mutation.

Gene_expression (expressing) of VCP in muscle associated with disease and apoptosis

12) Confidence 0.55 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 1.06 Pain Relevance 0

Western blot analysis of wild type and mutant quadriceps, brain, heart and liver tissues revealed similar VCP expression levels (Figure 1D,E).

Gene_expression (expression) of VCP in liver

13) Confidence 0.49 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.28 Pain Relevance 0

Western blot analysis of wild type and mutant quadriceps, brain, heart and liver tissues revealed similar VCP expression levels (Figure 1D,E).

Gene_expression (expression) of VCP in quadriceps

14) Confidence 0.17 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.28 Pain Relevance 0

Western blot analysis of wild type and mutant quadriceps, brain, heart and liver tissues revealed similar VCP expression levels (Figure 1D,E).

Gene_expression (expression) of VCP in heart

15) Confidence 0.17 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.28 Pain Relevance 0

Western blot analysis of wild type and mutant quadriceps, brain, heart and liver tissues revealed similar VCP expression levels (Figure 1D,E).

Gene_expression (expression) of VCP in brain

16) Confidence 0.17 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2950155 Disease Relevance 0.28 Pain Relevance 0

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