RGS4 Polymorphisms Predict Clinical Manifestations and Responses to Risperidone Treatment in Patients With Schizophrenia

Lane, Hsien‐Yuan; Liu, Yi-Ching; Huang, Chieh-Liang; Chang, Yue‐Cune; Wu, Po-Lun; Huang, Chiung-Hsien; Tsai, Guochuan E.

doi:10.1097/jcp.0b013e3181603f5a

Cited by 40 publications

(23 citation statements)

References 19 publications

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“…Rgs16 is involved in the regulation of circadian rhythms and in the regulation of islet survival and development of diabetes (13,45). Genetic variations in the Rgs4 gene are related to schizophrenia and mood disorders (16,22,37). As WS patients suffer from psychiatric disorders and from diabetes, the RGS pathway seems to be a biologically relevant target, based on our findings.…”

Section: Discussionmentioning

confidence: 70%

Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice

Kõks

Soomets

Plaas³

et al. 2011

Physiological Genomics

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The Wfs1 gene codes for a protein with unknown function, but deficiency in this protein results in a range of neuropsychiatric and neuroendocrine syndromes. In the present study we aimed to find the functional networks influenced by Wfs1 in the hypothalamus. We performed gene expression profiling (Mouse Gene 1.0 ST Arrays) in Wfs1-deficient mice; 305 genes were differentially expressed with nominal P value<0.01. FDR (false discovery rate)-adjusted P values were significant (0.007) only for two genes: C4b (t=9.66) and Wfs1 (t=-9.03). However, several genes related to G protein signaling were very close to the FDR-adjusted significance level, such as Rgs4 (regulator of G protein signaling 4) that was downregulated (-0.34, t=-5.4) in Wfs1-deficient mice. Changes in Rgs4 and C4b expression were confirmed by QRT-PCR. In humans, Rgs4 is in the locus for bipolar disease (BPD), and its expression is downregulated in BPD. C4b is a gene related to the neurodegenerative diseases. Functional analysis including the entire data set revealed significant alterations in the canonical pathway "G protein-coupled receptor signaling." The gene expression profile in the hypothalami of the Wfs1 mutant mice was significantly similar to the profiles of following biological functions: psychological disorders, bipolar disorder, mood disorder. In conclusion, hypothalamic gene expression profile resembles with some molecular pathways functionally related to the clinical syndromes in the Wolfram syndrome patients.

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Section: Discussionmentioning

confidence: 70%

Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice

Kõks

Soomets

Plaas³

et al. 2011

Physiological Genomics

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“…In a nonbiased gene array study, RGS4 was the most consistently altered transcript in the PFC of schizophrenia patients (Mirnics et al 2001). A postmortem study found significantly lower RGS4 mRNA and protein levels in the dlPFC of schizophrenia patients compared with healthy controls (Erdely et al 2006), and RGS4 SNPs predicted poorer performance on clinical ratings scales in a recent study performed in a population of Han-Chinese schizophrenia patients (Lane et al 2008). Reduced RGS4 in the dlPFC would lead to excessive protein kinase C signaling and impaired PFC cognitive function.…”

Section: Rgs4mentioning

confidence: 99%

“…Reduced RGS4 in the dlPFC would lead to excessive protein kinase C signaling and impaired PFC cognitive function. These patients also responded best to risperidone (Lane et al 2008), which reduces PI signaling by blocking extracellular receptors coupled to Gq (see below).…”

Section: Rgs4mentioning

confidence: 99%

The Neuropsychopharmacology of Fronto-Executive Function: Monoaminergic Modulation

Robbins

Arnsten

2009

Annu. Rev. Neurosci.

838

716

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We review the modulatory effects of the catecholamine neurotransmitters noradrenaline and dopamine on prefrontal cortical function. The effects of pharmacologic manipulations of these systems, sometimes in comparison with the indoleamine serotonin (5-HT), on performance on a variety of tasks that tap working memory, attentional-set formation and shifting, reversal learning, and response inhibition are compared in rodents, nonhuman primates, and humans using, in a behavioral context, several techniques ranging from microiontophoresis and single-cell electrophysiological recording to pharmacologic functional magnetic resonance imaging. Dissociable effects of drugs and neurotoxins affecting these monoamine systems suggest new ways of conceptualizing state-dependent fronto-executive functions, with implications for understanding the molecular genetic basis of mental illness and its treatment.

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“…However, subsequent findings support a role for RGS4 in both symptomology and pathophysiology. For example, a postmortem study found significantly lower mRNA and protein levels in the dlPFC of schizophrenia patients compared with healthy controls (Erdely et al 2006), and RGS4 SNPs predicted poorer performance on clinical ratings scales in a recent study performed in a population of Han-Chinese schizophrenia patients (Lane et al 2008).…”

Section: Rgs4mentioning

confidence: 99%

Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness

Hains¹,

Arnsten²

2008

Learn. Mem.

113

102

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The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via cAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of α1 receptors impairs prefrontal function via phosphatidylinositol–protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates cAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)—the molecule most associated with bipolar disorder— normally serve to inhibit phosphatidylinositol–protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory.

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RGS4 Polymorphisms Predict Clinical Manifestations and Responses to Risperidone Treatment in Patients With Schizophrenia

Abstract: These findings suggest that RGS4 variances influence clinical manifestations of schizophrenia as well as the treatment response to risperidone, suggesting that RGS4 plays a role in the fundamental process of disease pathophysiology.

Cited by 40 publications

References 19 publications

Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice

Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice

The Neuropsychopharmacology of Fronto-Executive Function: Monoaminergic Modulation

Molecular mechanisms of stress-induced prefrontal cortical impairment: Implications for mental illness

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