No Abnormality in the Gene for the G Protein Stimulatory α Subunit in Patients With Bipolar Disorder

Ram, Alpana; Guedj, Françoise; Cravchik, Anibal; Weinstein, Lee S.; Cao, Qiuhe; Badner, Judith A.; Goldin, Lynn R.; Grisaru, Nimrod; Manji, Husseini K.; Belmaker, Robert H.; Gershon, Elliot S.; Gejman, Pablo V.

doi:10.1001/archpsyc.1997.01830130048010

Cited by 50 publications

(24 citation statements)

References 27 publications

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“…34 Moreover, mutations in this gene in vulnerable or diseased patients are unlikely. 12 The promoter region of the ␣ s gene has been sequenced and characterized. 35 Its GC-content is extremely high (85%).…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11] There is no indication of mutations or other defects in the gene of the G protein subunit ␣ s in affective illness. 12 However, abnormalities in the expression of G protein ␣ subunits have been found in postmortem brains and peripheral blood cells from patients with bipolar affective disorder. [13][14][15] Alpha s immunoreactivity and forskolin-activated adenylyl cyclase activity was elevated in brains of these patients.…”

Section: Introductionmentioning

confidence: 99%

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Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

et al. 1998

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Disturbances of events associated with intracellular signaling pathways have been suspected of involvement in the development or progression of affective disorders. Often, heterotrimeric G proteins are located at the beginning of these pathways as modulators of extracellular messages. For this reason, messenger RNA expression of three G protein ␣-subunits and of phosphatidylinositol-3 kinase (PI-3 K) regulatory subunit p85 was examined in granulocytes from patients with bipolar or unipolar affective disorder and compared to healthy controls. Messenger RNA expression of the G protein subunit ␣ q and of p85 was identical in unipolar and bipolar patients and in controls. Furthermore, mRNAs of G protein subunits ␣ s and ␣ i2 were not different in unipolar patients as compared to healthy controls. Alpha s mRNA, however, was markedly increased in bipolar patients. This increase was observed in lithiumtreated (more than 12 months) and in unmedicated patients. Elevated levels of ␣ i2 mRNA in unmedicated bipolar patients did not reach statistical significance, whereas mRNA in bipolar patients receiving lithium was significantly above controls. Finally, long-term medication of unipolar patients with lithium had no influence on ␣ i2 mRNA levels. The data reveal elevated mRNA levels of G␣ s as a robust feature of bipolar affective disorder. Moreover, despite responsiveness of ␣ i2 gene expression to cAMP-related events, no substantial upregulation of ␣ i2 mRNA was observed in bipolar patients. The lack of ␣ i2 mRNA upregulation, hence, could be an additional abnormality in these patients. Even though lithium was able to reinstate this upregulation, there was no feedback downregulation of ␣ s . This strongly supports the notion of major disturbances of the cAMP signaling system in bipolar illness.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

et al. 1998

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“…Altered expression level of G protein AS and AI2 subunits (GNAS, GNAI2) in the post-mortem brains from bipolar or lithium receiving subjects has also been reported, 33 although variants in the former gene are not apparently associated with bipolar disorder. 34 Recent animal studies demonstrated that chronic administration of antidepressants induces elevation of cAMP-responsive element binding protein gene (CREB1) expression- 35 and cAMP-responsive element modulator (CREM)-deficient mice showed emotional and behavioral changes. 36 Also, chronic antidepressant administration increases cAMP phosphodiesterase (PDE4A and PDE4B) expression in rat frontal cortex.…”

Section: Neurotransmission Systemsmentioning

confidence: 99%

Genetic tests of biologic systems in affective disorders

et al. 2005

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To liberate candidate gene analyses from criticisms of inexhaustiveness of examination of specific candidate genes, or incompleteness in the choice of candidate genes to study for specific neurobiological pathways, study of sizeable sets of genes pertinent to each putative pathophysiological pathway is required. For many years, genes have been tested in a 'one by one' manner for association with major affective disorders, primarily bipolar illness. However, it is conceivable that not individual genes but abnormalities in several genes within a system or in several neuronal, neural, or hormonal systems are implicated in the functional hypotheses for etiology of affective disorders. Compilation of candidate genes for entire pathways is a challenge, but can reasonably be carried out for the major affective disorders as discussed here. We present here five groupings of genes implicated by neuropharmacological and other evidence, which suggest 252 candidate genes worth examining. Inexhaustiveness of gene interrogation would apply to many studies in which only one polymorphism per gene is analyzed. In contrast to whole-genome association studies, a study of a limited number of candidate genes can readily exploit information on genomic sequence variations obtained from databases and/or resequencing, and has an advantage of not having the complication of an extremely stringent statistical criterion for association. Molecular Psychiatry (2005) 10, 719-740.

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“…However, while Berrettini et al 4 reported two intronic polymorphisms in introns 3 and 10 of Golf␣, no significant differences were found between patients with bipolar disorder and controls in the frequency of the two 5 found three silent polymorphisms of Gs␣ in exons 5, 7, and 13, but again no allelic association between bipolar patients and controls was found for these three polymorphisms. However, no reported studies have considered associations between schizophrenia and G proteins.…”

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confidence: 90%

Association of a GTP-binding protein Goα subunit mutation with schizophrenia

Tani

Mui²,

Minami

et al. 2001

Mol Psychiatry

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SIR -The pathogenesis of schizophrenia has been suggested to involve not only dopaminergic overactivity but also abnormal function of signaling systems associated with second messengers.1 Go␣ is a member of the ␣ subunit family of GTP-binding proteins (G proteins), and interacts with muscarinic cholinergic, ␥-aminobutyric acid B, and dopamine D2 receptors. 2Tsukamoto et al 3 reported the sequence of human Go␣ genomic DNA. In the present study, we hypothesized that mutations in the Go␣ gene may be associated with the pathogenesis of schizophrenia.We investigated 175 unrelated Japanese patients (92 men and 83 women; mean age = 47.3 years, SD = 12.1) who met DSM-IV criteria for schizophrenia; 172 unrelated control subjects (76 men and 96 women; mean age = 41.8 years, SD = 12.7) were also studied. Written informed consent was obtained from all probands according to a research protocol approved by the ethics committee of Osaka City University Medical School. Using single strand conformational polymorphism (SSCP), one missense mutation, ATG→ACG (Met129→Thr129) in exon 4, and two silent mutations, ACT→ACC (Thr171) in exon 5 and AAA→AAG (Lys317) in exon 8B, were found in the Go␣ gene among patients with schizophrenia. The genotype distribution for each mutation was not significantly different from the distribution expected according to Hardy-Weinberg equilibrium. While silent mutations were not associated with schizophrenia (data not shown), significant excesses of the missense mutation in genotype (P = 0.012, 2 = 6.313, df = 1) and allele frequencies (P = 0.013, 2 = 6.193, df = 1) were found in patients compared with controls (Table 1).Some polymorphisms in human G protein genes have been suggested to confer susceptibility to bipolar disorder. However, while Berrettini et al 4 reported two intronic polymorphisms in introns 3 and 10 of Golf␣, no significant differences were found between patients with bipolar disorder and controls in the frequency of the two showed that a mutant form of Go␣ in which Trp132 was replaced by Phe showed a two-fold reduction in GDP dissociation rate. Trp132 is located in helix C of the ␣-helical domain which is considered with a GTPase activating protein domain, 7 only three residues downstream of the presently described missense mutation. We therefore believe that the missense mutation influences activity of adenylyl cyclase or GTP hydrolysis in Go␣ protein. As Go␣ interacts with several neurotransmitter receptors including dopamine D2 receptors, the missense mutation could be associated with abnormalities of multiple signaling systems, including dopaminergic overactivity.In conclusion, our results indicated that the missense mutation may play a pathogenetic role in a subset of patients with schizophrenia, rather than in most patients, since allele frequencies were small (schizophrenia, 0.031; control, 0.006). Further studies are needed in larger numbers of patients to elucidate the association of this missense mutation of Go␣ protein with clinical features and types of schizophrenia.

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No Abnormality in the Gene for the G Protein Stimulatory α Subunit in Patients With Bipolar Disorder

Abstract: Our results do not support the speculation that the Gs-alpha protein gene has a role in the genetic predisposition to bipolar disorder.

Cited by 50 publications

References 27 publications

Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

Genetic tests of biologic systems in affective disorders

Association of a GTP-binding protein Goα subunit mutation with schizophrenia

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