Assessment of de novo copy-number variations in Italian patients with schizophrenia: Detection of putative mutations involving regulatory enhancer elements

Piluso, Giulio; Monteleone, Palmiero; Galderisi, Silvana; Giugliano, Teresa; Bertolino, Alessandro; Rocca, Paola; Rossi, Alessandro; Mucci, Armida; Aguglia, Eugenio; Andriola, Ileana; Bellomo, Antonello; Comparelli, Anna; Gambi, Francesco; Fagiolini, Andrea; Marchesi, Carlo; Roncone, Rita; Sacchetti, Emilio; Santonastaso, Paolo; Siracusano, Alberto; Stratta, Paolo; Tortorella, Alfonso; Steardo, Luca; Bucci, Paola; Nigro, Vincenzo; Maj, Mario

doi:10.1080/15622975.2017.1395072

Cited by 11 publications

(12 citation statements)

References 85 publications

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“…Common features are positive symptoms, such as hallucinations, delusions, disorganized speech, and negative symptoms, such as social deficits, lack of motivation, anhedonia, and impaired emotion processing, as well as cognitive deficits with occupational dysfunction (Arajarvi et al, 2005). Previous studies have reported various copy number variations (CNVs) related to schizophrenia (Piluso et al, 2017; Zhuo et al, 2017). Several recent studies have suggested that the rit2 gene might be involved in the pathogenesis of schizophrenia (Glessner et al, 2010).…”

Section: The Ras Family In Non-neoplastic Cerebral Diseasesmentioning

confidence: 99%

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Qu¹,

Pan²,

et al. 2019

Front. Mol. Neurosci.

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The small GTPases from the Ras superfamily play crucial roles in basic cellular processes during practically the entire process of neurodevelopment, including neurogenesis, differentiation, gene expression, membrane and protein traffic, vesicular trafficking, and synaptic plasticity. Small GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Different subfamilies of small GTPases have been linked to a number of non-neoplastic cerebral diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), intellectual disability, epilepsy, drug addiction, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and a large number of idiopathic cerebral diseases. Here, we attempted to make a clearer illustration of the relationship between Ras superfamily GTPases and non-neoplastic cerebral diseases, as well as their roles in the neural system. In future studies, potential treatments for non-neoplastic cerebral diseases which are based on small GTPase related signaling pathways should be explored further. In this paper, we review all the available literature in support of this possibility.

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Section: The Ras Family In Non-neoplastic Cerebral Diseasesmentioning

confidence: 99%

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Qu¹,

Pan²,

et al. 2019

Front. Mol. Neurosci.

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“…The neurophysiological roles of Magi-1 are largely unknown; however, human genetic studies have revealed that MAGI-1 mutations are associated with psychiatric disease, particularly schizophrenia (24)(25)(26). Notably, the extensive and diverse literature of clinical and experimental reports suggests that many individuals with schizophrenia are less sensitive to pain than normal individuals (27).…”

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confidence: 99%

“…C ) Quantification of peak I Na and TTX-resistant peak I Na (at voltage step 220 mV) after Magi-1 knockdown. A total of 9-12 cells per experimental group were analyzed, and values are expressed as means 6 SEM [ANOVA, F(3,26) = 66.24]. *P , 0.0106, ***P , 0.001 vs. respective controls (scrambled siRNA with or without TTX).…”

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confidence: 99%

Magi‐1 scaffolds Na _v 1‐8 and Slack K _Na channels in dorsal root ganglion neurons regulating excitability and pain

et al. 2019

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Voltage‐dependent sodium (Nav) 1.8 channels regulate action potential generation in nociceptive neurons, identifying them as putative analgesic targets. Here, we show that Nav1.8 channel plasma membrane localization, retention, and stability occur through a direct interaction with the postsynaptic density‐95/discs large/zonula occludens‐l‐and WW domain‐containing scaffold protein called membrane‐associated guanylate kinase with inverted orientation (Magi)‐l. The neurophysiological roles of Magi‐1 are largely unknown, but we found that dorsal root ganglion (DRG)‐specific knockdown of Magi‐1 attenuated thermal nociception and acute inflammatory pain and produced deficits in Nav1.8 protein expression. A competing cell‐penetrating peptide mimetic derived from the Nav1.8 WW binding motif decreased sodium currents, reduced Nav1.8 protein expression, and produced hypoexcitability. Remarkably, a phosphorylated variant of the very same peptide caused an opposing increase in Nav1.8 surface expression and repetitive firing. Likewise, in vivo, the peptides produced diverging effects on nocifensive behavior. Additionally, we found that Magi‐1 bound to sequence like a calcium‐activated potassium channel sodium‐activated (Slack) potassium channels, demonstrating macrocomplexing with Nav1.8 channels. Taken together, these findings emphasize Magi‐1 as an essential scaffold for ion transport in DRG neurons and a central player in pain.—Pryce, K. D., Powell, R., Agwa, D., Evely, K. M., Sheehan, G. D., Nip, A., Tomasello, D. L., Gururaj, S., Bhattacharjee, A. Magi‐1 scaffolds Nav1.8 and Slack KNa channels in dorsal root ganglion neurons regulating excitability and pain. FASEB J. 33, 7315–7330 (2019). http://www.fasebj.org

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“…Erg (ETS transcription factor) was expressed at low levels (1.4–2 FPKM) in the nucleus accumbens samples and declined in ovariectomized mice treated with estradiol. Magi1 (membrane-associated guanylate kinase 1), which was recently found to have copy number variants associated with schizophrenia [56], is a downstream target in two of the estradiol-regulated pathways. Dctpp1 was also identified as a downstream target of Myc in the male-female pairing (Fig.…”

Section: Resultsmentioning

confidence: 99%

Sex-Specific Gene Expression in the Mouse Nucleus Accumbens Before and After Cocaine Exposure

LaRese

Rheaume

Abraham

et al. 2019

Journal of the Endocrine Society

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The nucleus accumbens plays a major role in the response of mammals to cocaine. In animal models and human studies, the addictive effects of cocaine and relapse probability have been shown to be greater in females. Sex-specific differential expression of key transcripts at baseline and after prolonged withdrawal could underlie these differences. To distinguish between these possibilities, gene expression was analyzed in four groups of mice (cycling females, ovariectomized females treated with estradiol or placebo, and males) 28 days after they had received seven daily injections of saline or cocaine. As expected, sensitization to the locomotor effects of cocaine was most pronounced in the ovariectomized mice receiving estradiol, was greater in cycling females than in males, and failed to occur in ovariectomized/placebo mice. After the 28-day withdrawal period, RNA prepared from the nucleus accumbens of the individual cocaine- or saline-injected mice was subjected to RNA sequencing analysis. Baseline expression of 3% of the nucleus accumbens transcripts differed in the cycling female mice compared with the male mice. Expression of a similar number of transcripts was altered by ovariectomy or was responsive to estradiol treatment. Nucleus accumbens transcripts differentially expressed in cycling female mice withdrawn from cocaine exhibited substantial overlap with those differentially expressed in cocaine-withdrawn male mice. A small set of transcripts were similarly affected by cocaine in the placebo- or estradiol-treated ovariectomized mice. Sex and hormonal status have profound effects on RNA expression in the nucleus accumbens of naive mice. Prolonged withdrawal from cocaine alters the expression of a much smaller number of common and sex hormone-specific transcripts.

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Assessment of de novo copy-number variations in Italian patients with schizophrenia: Detection of putative mutations involving regulatory enhancer elements

Abstract: These findings provide further evidence for the involvement of de novo CNVs in the pathogenesis of schizophrenia and suggest that CNVs affecting regulatory enhancer elements could contribute to the genetic vulnerability to the disorder.

Cited by 11 publications

References 85 publications

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Magi‐1 scaffolds Na _v 1‐8 and Slack K _Na channels in dorsal root ganglion neurons regulating excitability and pain

Sex-Specific Gene Expression in the Mouse Nucleus Accumbens Before and After Cocaine Exposure

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Assessment of de novo copy-number variations in Italian patients with schizophrenia: Detection of putative mutations involving regulatory enhancer elements

Abstract: These findings provide further evidence for the involvement of de novo CNVs in the pathogenesis of schizophrenia and suggest that CNVs affecting regulatory enhancer elements could contribute to the genetic vulnerability to the disorder.

Cited by 11 publications

References 85 publications

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

The Ras Superfamily of Small GTPases in Non-neoplastic Cerebral Diseases

Magi‐1 scaffolds Na v 1‐8 and Slack K Na channels in dorsal root ganglion neurons regulating excitability and pain

Sex-Specific Gene Expression in the Mouse Nucleus Accumbens Before and After Cocaine Exposure

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Product

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Magi‐1 scaffolds Na _v 1‐8 and Slack K _Na channels in dorsal root ganglion neurons regulating excitability and pain