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

For several decades, lithium has been the drug of choice in the long-term t reatment of manic-depressive illness, but the molecular mechanism(s) mediat ing its therapeutic effects remain to be determined, The enzyme myo-inosito l monophosphatase (IMPase) in the phospholipase C signaling system is inhib ited by lithium at therapeutically relevant concentrations, and is a candid ate target of lithium's mood-stabilizing action. Two genes encoding human I MPases have so far been isolated, namely IMPA1 on chromosome 8q21.13-21.3 a nd IMPA2 on chromosome 18p11.2. Interestingly, several studies have indicat ed the presence of a susceptibility locus for bipolar disorder on chromosom e 18p11.2. IMPA2 is therefore a candidate for genetic studies on both etiol ogy 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 Spl elements and lacks a TATA-box, features typical for housekeeping genes. By a preliminar y polymorphism screening of exons 2-8 in a sample of 23 Norwegian bipolar p atients, we have identified nine single nucleotide polymorphisms (SNPs). Se ven of the polymorphisms were located in the introns, one was a silent tran sition in exon 2 (159T>C) and one was a transition in exon 5 (443G>A) resul ting in a predicted amino acid substitution (R148Q). Our data show that eve n in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified. IMPA2 is therefore an intriguing candidate gene for fut ure association studies of manic-depressive illness.