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

Recently, we cloned the human myo-inositol monophosphatase 2 (IMPA2) cDNA a nd established its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder. Because the myo-inositol monophosphatase en zyme has been shown to be inhibited by lithium, an effective therapeutic ag ent for bipolar disorder, IMPA2 is a plausible positional and functional ca ndidate gene. To permit comprehensive screening for variants we characteriz ed the genomic structure and isolated the potential promoter of IMPA2 The g ene was found to encode eight exons spanning similar to 27 kb, The proximal 1-kb 5' flanking region did not contain an obvious TATA box but multiple p otential binding sites for Spl and consensus motifs for AP2 and other trans cription factors were evident. Sequencing of the coding region and splice j unctions in unrelated bipolar disorder patients detected novel variants. A missense mutation in exon 2, His76Tyr, was found in one patient. His76 is e volutionarily conserved and replacement with Tyr introduces a potential sit e for phosphorylation. The other polymorphisms included an Rsal polymorphis m, IVS1-15G>A, and a T --> C silent mutation in the third nucleotide of cod on 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 s crutiny of this gene is warranted.