Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lithium is used in the clinical treatment of bipolar disorder, a disease where patients suffer mood swings between mania and depression. Although the mode of action of lithium remains elusive, a putative primary target is thought to be inositol monophosphatase (IMPase) activity. Two IMPase genes have been identified in mammals, the well characterized myo-inositol monophosphatase 1 (IMPA1) and myo-inositol monophosphatase 2 (IMPA2). Several lines of genetic evidence have implicated IMPA2 in the pathogenesis of not only bipolar disorder but also schizophrenia and febrile seizures. However, little is known about the protein, although it is predicted to have lithium-inhibitable IMPase activity based on its homology to IMPA1. Here we present the first biochemical study comparing the enzyme activity of IMPA2 to that of IMPA1. We demonstrate that in vivo, IMPA2 forms homodimers but no heterodimers with IMPA1. Recombinant IMPA2 exhibits IMPase activity, although maximal activity requires higher concentrations of magnesium and a higher pH. IMPA2 shows significantly lower activity toward myo-inositol monophosphate than IMPA1. We therefore screened for additional substrates that could be more efficiently dephosphorylated by IMPA2, but failed to find any. Importantly, when using myo-inositol monophosphate as a substrate, the IMPase activity of IMPA2 was inhibited at high lithium and restricted magnesium concentrations. This kinetics distinguishes it from IMPA1. We also observed a characteristic pattern of differential expression between IMPA1 and IMPA2 in a selection of tissues including the brain, small intestine, and kidney. These data suggest that IMPA2 has a separate function in vivo from that of IMPA1.
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PMID:Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1. 1706 42

The human IMPA2 gene, which encodes myo-inositol monophosphatase 2 (IMPA2), is mapped onto 18p11.2, a susceptibility region for bipolar disorder. This chromosomal region has also been proposed to include a susceptibility locus for schizophrenia and febrile seizures. Here we report the crystal structures of human IMPA2 and its complex with calcium and phosphate ions. Human IMPA2 comprises an alpha-beta protein with a five-layered sandwich of alpha-helices and beta-sheets (alpha-beta-alpha-beta-alpha). The crystal structure and analytical ultracentrifugation results indicated that IMPA2 exists as a dimer in solution. The overall structure of IMPA2 is similar to that of IMPA1, except for the loop regions. In IMPA1, the loop region (31-43) is located at the entrance of the active site cavity. In the corresponding region (42-54) of IMPA2, the residues are disordered and partially form an alpha-helix. The structural difference in the opening of the active site cavity suggests that the substrate specificity differs between IMPA1 and IMPA2. The widely opened cavity of IMPA2 implies that the physiological substrate may be a larger compound than inositol monophosphate. The structure of IMPA2 complexed with Ca2+ revealed two metals and one phosphate binding sites, which were the same sites as in IMPA1 complexed with Mn2+ and phosphate, suggesting that the mechanism of the enzymatic reaction is similar to that of IMPA1. The crystal structures of human IMPA2 are useful for understanding the effect of nonsynonymous polymorphism reported in IMPA2, and will contribute to further functional analyses of IMPA2 that potentially predisposes to the vulnerabilities of bipolar disorder, schizophrenia, and febrile seizures.
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PMID:Crystal structure of human myo-inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures. 1734 Jun 35

Pathogenesis of febrile seizures (FS), causing the most common of types of seizures in children, remains unknown. Genetic factors appear to play a pivotal role and FS can be inherited as a monogenic or genetically complex disorder. Several risks factors have been proposed but many of the previously reported genetic associations were not replicated. Non-coding polymorphisms in the myo-inositol monophosphatase 2 gene (IMPA2) have been suggested as a susceptibility factor for FS in Japanese patients. It is unknown whether genetic variants in the same gene constitute a risk factor for FS in other ethnic groups because the frequency of FS is significantly higher in Japanese children than in Caucasian patients. We investigated the role of the IMPA2 gene in a cohort of 96 unrelated Caucasian subjects with a history of FS. We did not identify any significant differences in genotypes of cases and matched controls; no mutations or non-synonymous polymorphisms were detected in these individuals. Our data suggest that the genetic variants in the IMPA2 gene are not associated with a risk of FS in Caucasian patients and patients from various genetic groups are likely to have different genetic causes of FS.
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PMID:Genetic variants in the IMPA2 gene do not confer increased risk of febrile seizures in Caucasian patients. 1738 92