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

Abstract

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.

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

“…The interpretation of the inositol depletion hypothesis has been complicated further by the discovery of a second gene coding for IMPase named IMPA2 (Sjoholt et al, 2000;Yoshikawa et al, 2000). 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).…”

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

“…It was clear that the four SNPs that we chose initially were too rare and unsuitable to perform LD mapping of the gene. Therefore, we chose three further SNPs: 599 þ 97G4A and 599 þ 99G4A had been reported by Sjoholt et al, 11 and rs3786282 was selected from the public Figure 1). All three SNPs appeared to have minor allele frequencies B30% and we could be confident that they were going to be informative in our populations.…”

“…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. 13 Linkage studies 14,15 have suggested the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2.…”

“…13 Linkage studies 14,15 have suggested the presence of a susceptibility locus for bipolar disorder on chromosome 18p11.2. The gene has been screened for polymorphisms and tested for association with BP 11,12 and schizophrenia. 16 Yoshikawa et al 12 described only three polymorphisms: 97À15G4A, 159T4C and 226C4T (His76Tyr), and tested their frequencies in 96 BP individuals and 59 unrelated persons from CEPH families.…”

“…These single-nucleotide polymorphisms (SNPs) were reported as rare and differences did not reach statistical significance; however, the study was clearly underpowered to detect a more modest effect. Sjoholt et al 11 screened the gene in 23 individuals affected with BP and identified six previously unreported polymorphisms (230 þ 141G4A, 382À44G4A, 443G4A, 599 þ 75 delT, 599 þ 97G4A, 599 þ 99G4A), as well as 97À15G4A and 159T4C reported in Yoshikawa et al 12 (throughout the present paper we use the nomenclature used by Sjoholt et al, 11 so that for example, 58G4A, described by Yoshikawa et al 16 becomes À185G4A, etc). Yoshikawa et al 16 found seven other SNPs and tested À185G4A, 97À15G4A and 558C4T (the last one is now in the public databases as rs2075825) for association in 302 schizophrenics, 105 bipolar patients and 308 controls from Japan.…”