Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2)

Abstract

Recently, we cloned the human myo-inositol monophosphatase 2 (IMPA2) cDNA and established its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder. Because the myo-inositol monophosphatase enzyme has been shown to be inhibited by lithium, an effective therapeutic agent for bipolar disorder, IMPA2 is a plausible positional and functional candidate gene. To permit comprehensive screening for variants we characterized the genomic structure and isolated the potential promoter of IMPA2. The gene was found to encode eight exons spanning ෂ27 kb. The proximal 1-kb 5Ј flanking region did not contain an obvious TATA box but multiple potential binding sites for Sp1 and consensus motifs for AP2 and other transcription factors were evident. Sequencing of the coding region and splice junctions in unrelated bipolar disorder patients detected novel variants. A missense mutation in exon 2, His76Tyr, was found in one patient. His76 is evolutionarily conserved and replacement with Tyr introduces a potential site for phosphorylation. The other polymorphisms included an RsaI polymorphism, IVS1-15GϾA, and a T → C silent mutation in the third nucleotide of codon 53 in exon 2. By Fisher's exact test the silent mutation showed a trend for association (P = 0.051) with bipolar disorder suggesting that further scrutiny of this gene is warranted. Molecular Psychiatry (2000) 5, 165-171.

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).…”

Dense SNP association study for bipolar I disorder on chromosome 18p11 suggests two loci with excess paternal transmission

“…A number of candidate genes on chromosome 18p11 have been investigated for association with genetic markers, including NAPG, PACAP, MC5R, IMPA2, NDUFV2, GNAL and CLUL1 [13][14][15][16][17][18][19][20][21] (Table 1).…”

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

“…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.…”