title: 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;27 kb. The proximal 1-kb 5' 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, IVS1-15G>A, 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.
authors.affiliation: Unit on Gene Mapping and Expression, Clinical Neurogenetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: M
authors.initials: M
authors.lastname: Padigaru
authors.forename: J D
authors.initials: JD
authors.lastname: Karkera
authors.forename: M
authors.initials: M
authors.lastname: Sharma
authors.forename: W H
authors.initials: WH
authors.lastname: Berrettini
authors.forename: L E
authors.initials: LE
authors.lastname: Esterling
authors.forename: S D
authors.initials: SD
authors.lastname: Detera-Wadleigh
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D001714:Bipolar Disorder / Q000201:enzymology / Q000235:genetics*; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18; D005091:Exons; D005260:Female; D015723:Gene Library; D014644:Genetic Variation; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase