Inositol monophosphatase in immortalized lymphoblastoid cell lines indicates susceptibility to bipolar disorder and response to lithium therapy

Shamir, Alon; Ebstein, Richard P.; Nemanov, Lubov; Zohar, Anat; Belmaker, Robert H.; Agam, Galila

doi:10.1038/sj.mp.4000470

Cited by 47 publications

(35 citation statements)

References 8 publications

(13 reference statements)

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“…This includes inositol monophosphatase (Shamir et al 1998), diphosphoinositol polyphosphate phosphohydrolase II (Hua et al 2001), sodium/myo-inositol cotransporter (Lubrich and van Calker 1999), aldolase A (Hua et al 2000) and C isozymes (Hua and Li, unpublished), prolyl oligopeptidase (Williams et al 1999), and CD151 (present study). Such a cluster of changes is unlikely a chance event.…”

Section: Discussionmentioning

confidence: 67%

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Hua

Green

Wong

et al. 2001

Neuropsychopharmacology

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The latency in onset of antimanic and mood stabilizing effects of lithium suggest that long-term neuronal adaptations mediated by changes in gene expression may be important to the therapeutic action of lithium treatment. Using differential display-polymerase chain reaction, several novel, hitherto unexpected lithium-regulated genes have been isolated, all of which would not have beenAlthough lithium is widely used in the treatment of acute mania and the prophylaxis for bipolar affective disorder, the cellular and molecular mechanisms underlying its therapeutic action remain unclear. However, significant progress has been made over the past decade with cumulative evidence indicating that modulation of postreceptor signaling mechanisms in critical regions of the brain may be essential to the mood stabilizing properties of this agent (reviewed in Jope 1999;Li et al. 2000;Manji and Lenox 1999).Many signal transduction cascades are known to induce long-term cellular responses through regulation of gene transcription. Moreover, the delayed onset of therapeutic action of lithium has led to the hypothesis that regulation of gene expression may be important for its mood stabilizing effects (Jope 1999;Li et al. 2000). In line with this hypothesis, several studies have demonstrated that chronic lithium treatment alters the expression of an array of genes, including G protein ␣ -subunits, adenylyl cyclase subtypes, neuropeptides (reviewed in Jope 1999;Li et al. 2000;Manji and Lenox 1999) NO . 5 et al. 2000). The modulatory effects of lithium on gene expression have been suggested to be mediated, at least in part, through the cAMP response element binding protein (CREB) or activator protein-1 (AP-1) transcriptional factor pathway (Ozaki and Chuang 1997;Asghari et al. 1998;Yuan et al. 1998). It is thus conceivable that other genes containing the consensus sequences for these transcription factors in their promoter region may also be the potential targets of lithium. Therefore, the identification of other lithium-regulated genes is important in better understanding the spectrum of cellular and molecular mechanisms that contribute to the therapeutic and/or side effects of this drug.Using differential display-polymerase chain reaction (ddPCR), several novel lithium-regulated genes have been identified that would not otherwise have been considered using a candidate gene approach. These novel lithium-regulated targets included 2 Ј , 3 Ј -cyclic nucleotide 3 Ј -phosphodiesterase type II (Wang and Young 1996), polyomavirus enhancer-binding protein 2 ␤ (Chen et al. 1999), nitrogen permease regulator 2 (Wang et al. 1999), aldolase A (Hua et al. 2000, and diphosphoinositol polyphosphate phosphohydrolase II (Hua et al. 2001). Unexpectedly, during the course of experiments amplifying the 5 Ј end of a putative lithium-regulated ddPCR fragment, we isolated another cDNA clone, a homolog of human/mouse transmembrane-4-superfamily (TM4SF) protein, CD151. The transcript levels of CD151 were significantly decreased in the rat frontal corte...

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Section: Discussionmentioning

confidence: 67%

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Hua

Green

Wong

et al. 2001

Neuropsychopharmacology

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“…Three of the promoter variants (À241_À237dup, À207T4C and À185A4G) are present in a region of alternative transcription start sites, 12,13 where À241_À237dup represents the five first nucleotides of the transcript reported by Yoshikawa et al 29 The À207T4C polymorphism is localized in a putative MZF1 regulatory site. 28 There is some evidence for altered IMPase enzyme activity 21 and changes in the IMPA2 expression levels 23 in bipolar patients compared to control individuals. These differences could possibly be explained by DNA variants in the regulative regions of the IMPA2 promoter and/or the 5 0 -UTR of the mRNA transcript.…”

Section: Impa2mentioning

confidence: 99%

“…Other studies have found some evidence for altered IMPase enzyme activity and changes in IMPA1 and myo-inositol monophosphatase 1 (IMPA2) expression levels in bipolar patients. [21][22][23] Moreover, lithium treatment of bipolar patients leads to a reduction in myo-inositol levels in certain brain regions. 24,25 It was recently published that the three mood-stabilizing drugs lithium, valproate and carbamazepine inhibited the collapse of growth cones and increased the growth cone area in sensory neurons.…”

Section: Introductionmentioning

confidence: 99%

Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder

et al. 2003

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Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (À461C4T and À207T4C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder.

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“…22 In line with these results, the enzyme activity of IMPase in transformed lymphoblastoid cell lines was reported to be lower in cells from bipolar patients than in cells from control individuals. 23 When the bipolar patients were grouped according to their clinical response to lithium therapy, the lithium responders exhibited significantly lower IMPase activity than the patients with poor lithium response. Since the IMPA2 gene maps to a putative susceptibility region for bipolar disorder and possibly encodes a lithium-inhibited IMPase, it should become the target for genetic studies of both lithium action and the pathophysiology of manic-depressive illness.…”

Section: Introductionmentioning

confidence: 99%

A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients

Sjøholt¹,

Gulbrandsen²,

Løvlie³

et al. 2000

Mol Psychiatry

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For several decades, lithium has been the drug of choice in the long-term treatment of manicdepressive illness, but the molecular mechanism(s) mediating its therapeutic effects remain to be determined. The enzyme myo-inositol monophosphatase (IMPase) in the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action. Two genes encoding human IMPases have so far been isolated, namely IMPA1 on chromosome 8q21.13-21.3 and IMPA2 on chromosome 18p11.2. Interestingly, several studies have indicated the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2. IMPA2 is therefore a candidate for genetic studies on both etiology and lithium treatment of manic-depressive illness. Here we report that the genomic structure of IMPA2 is composed of eight exons, ranging in size from 46 bp to 535 bp. The promoter region contains several Sp1 elements and lacks a TATA-box, features typical for housekeeping genes. By a preliminary polymorphism screening of exons 2-8 in a sample of 23 Norwegian bipolar patients, we have identified nine single nucleotide polymorphisms (SNPs). Seven of the polymorphisms were located in the introns, one was a silent transition in exon 2 (159TϾC) and one was a transition in exon 5 (443GϾA) resulting in a predicted amino acid substitution (R148Q). Our data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified. IMPA2 is therefore an intriguing candidate gene for future association studies of manic-depressive illness. Molecular Psychiatry (2000) 5, 172-180.

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Inositol monophosphatase in immortalized lymphoblastoid cell lines indicates susceptibility to bipolar disorder and response to lithium therapy

Cited by 47 publications

References 8 publications

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder

A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients

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