A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder

Yoshikawa, Takeo; Turner, Gordon; Esterling, Lisa E.; Sanders, Alan R.; Detera-Wadleigh, S D

doi:10.1038/sj.mp.4000325

Cited by 54 publications

(48 citation statements)

References 6 publications

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“…IMPA2 is located on chromosome 18 near a region implicated in linkage studies of manic depressive illness (Berrettini et al, 1994;Rojas et al, 2000). IMPA2 produces an mRNA transcript but has been shown to produce IMPase activity (Yoshikawa et al, 1997;Ohnishi et al, 2007). We have recently reported that IMPA2 KO mice have lower kidney inositol levels suggesting that the IMPA2 gene contributes to kidney IMPase activity.…”

Section: Introductionmentioning

confidence: 99%

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

Cryns¹,

Shamir

Acker

et al. 2007

Neuropsychopharmacol

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Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1 À/À ) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1 À/À mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1 À/À mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1 À/À mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1 À/À mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

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Section: Introductionmentioning

confidence: 99%

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

Cryns¹,

Shamir

Acker

et al. 2007

Neuropsychopharmacol

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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.…”

Section: Impa2mentioning

confidence: 99%

“…12 Recently, a gene on chromosome 18p11.2, named IMPA2, was predicted to encode an IMPase of high similarity to the IMPA1-encoded protein, especially in the active site and the ion-binding regions. 12,13 However, the IMPA2-encoded protein has not yet been isolated or functionally characterized.…”

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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“…8,9 Two genes encoding human IMPases have been identified: IMPA1 and IMPA2. IMPA2 was proposed as a plausible candidate gene by Yoshikawa et al, 10 because of its location within a region of positive linkage findings to BP 14,15 and the possible functional role of the inositol phospholipid signalling system. Yoshikawa et al 16 reported that the group of haplotypes containing either À185A, 97-15G or 558C have significantly higher frequencies in schizophrenics, but not in bipolar disorder patients from Japan.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 Myo-inositol monophosphatase 2 (IMPA2) codes for a second human myo-inositol monophosphatase. The gene has been mapped to chromosome 18p11.2 10 and its structure has been characterized. 11,12 The gene is a potential biochemical target for the action of lithium.…”

Section: Introductionmentioning

confidence: 99%

Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment

et al. 2004

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Lithium is the most effective mood-stabilizing drug in the therapy of bipolar affective disorder (BP). It is thought to exert its effect via the phosphatidylinositol signalling system. Myo-inositol monophosphatase 2 (IMPA2) codes for an enzyme in this system that is inhibited by lithium. It is located on 18p11.2, a region implicated as a BP susceptibility locus. We examined eight single-nucleotide polymorphisms (SNPs) identified within this gene for association with BP, using 237 parents-offspring trios and in 174 cases and 170 controls. No SNP showed association with BP. When good responders to lithium treatment were compared with the poor responders, some statistically significant differences emerged for two SNPs; however, the sample became too small to draw definitive conclusions. We cannot find support for the involvement of variation in IMPA2 in susceptibility to bipolar disorder, but the role of this and other genes from the phosphoinositol signalling pathway in predicting response to lithium treatment merits further investigation.

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A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder

Abstract: susceptibility region forWe performed a search for new ESTs, sequence tag sites (STSs) and genes in the general area of 18p11.2, bipolar disorder utilizing the transcript database 7 and updates in Uni-

Cited by 54 publications

References 6 publications

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

IMPA1 is Essential for Embryonic Development and Lithium-Like Pilocarpine Sensitivity

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

Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment

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