Yoshikawa T, Turner G, Esterling L E, Sanders A R, Detera-Wadleigh S D
Unit on Gene Mapping and Expression, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Psychiatry. 1997 Sep;2(5):393-7. doi: 10.1038/sj.mp.4000325.
Within the broad susceptibility region for bipolar disorder on the pericentromeric portion of chromosome 18, the highest allele sharing in our 22-pedigree series has been found in markers mapping to 18p11.2. Studies by other investigators on independently ascertained pedigrees have also shown increased sharing in this region, making 18p11.2 a plausible site for a candidate gene search. We found expressed sequence tags (ESTs) mapping within this area that are homologous to the myo-inositol-1-phosphate phosphohydrolase (myo-inositol monophosphatase: IMP) gene of Xenopus laevis. Since IMP has been proposed to be the potential target of lithium, a drug commonly used for the treatment of bipolar disorder, we proceeded to characterize the cognate transcript. Northern blot analysis detected a major transcript of 1.5 kb with abundant expression in adult and fetal tissues, but minimal expression in whole brain. In subcortical brain regions, however, substantial levels of transcript were evident, most prominently in the caudate. We have isolated and sequenced the full-length cDNA. The deduced amino acid sequence revealed approximately 54% identity with an existing human IMP, which we found mapped to chromosome 8, and IMP of other species. The sequence also included motifs characteristic of the IMP gene family. To provide a more precise location of this gene, mapping with a panel of radiation hybrids (RH) was conducted. Multipoint RH analysis placed the gene between GNAL and D18S71 within the 18p11.2 region. We, therefore, designated this novel gene as IMP.18p. The physical position and possible function suggest that IMP.18p is an important candidate gene for bipolar disorder.
在18号染色体着丝粒周围区域的双相情感障碍广泛易感区内，我们对22个家系进行的研究发现，在定位到18p11.2的标记中，等位基因共享程度最高。其他研究人员对独立确定的家系进行的研究也表明，该区域的共享程度增加，这使得18p11.2成为候选基因搜索的一个合理位点。我们发现该区域内的表达序列标签（EST）与非洲爪蟾的肌醇-1-磷酸磷酸水解酶（肌醇单磷酸酶：IMP）基因同源。由于IMP被认为是锂盐（一种常用于治疗双相情感障碍的药物）的潜在靶点，我们继续对相关转录本进行表征。Northern印迹分析检测到一个1.5kb的主要转录本，在成年和胎儿组织中表达丰富，但在全脑中表达极少。然而，在皮质下脑区，转录本水平明显较高，最显著的是在尾状核中。我们已经分离并测序了全长cDNA。推导的氨基酸序列显示与现有的人IMP（我们发现其定位于8号染色体）以及其他物种的IMP具有约54%的同一性。该序列还包含IMP基因家族的特征基序。为了更精确地定位该基因，我们使用了一组辐射杂种（RH）进行定位。多点RH分析将该基因定位在18p11.2区域内的GNAL和D18S71之间。因此，我们将这个新基因命名为IMP.18p。其物理位置和可能的功能表明IMP.18p是双相情感障碍的一个重要候选基因。
