A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder

  title={A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder},
  author={Takeo Yoshikawa and G Turner and Lisa Esterling and Alan R. Sanders and S. D. Detera-Wadleigh},
  journal={Molecular Psychiatry},
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… 

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

The data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified, and this gene is an intriguing candidate gene for future association studies of manic-depressive illness.

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

The human myo-inositol monophosphatase 2 (IMPA2) cDNA was cloned and its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder, and the genomic structure and potential promoter were characterized and isolated.

Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples

It is suggested that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese and increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity.

A Promoter Haplotype of the Inositol Monophosphatase 2 Gene (IMPA2) at 18p11.2 Confers a Possible Risk for Bipolar Disorder by Enhancing Transcription

It is suggested that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA1 levels in the brain, albeit the genetic effect varies among populations.

Crystal structure of human myo‐inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures

The crystal structures of human IMPA2 are useful for understanding the effect of nonsynonymous polymorphism reported in IMPA1, and will contribute to further functional analyses of IMPA3 that potentially predisposes to the vulnerabilities of bipolar disorder, schizophrenia, and febrile seizures.

Association analysis between polymorphisms in the myo-inositol monophosphatase 2 (IMPA2) gene and bipolar disorder

Association study of myo-inositol monophosphatase 2 (IMPA2) polymorphisms with bipolar affective disorder and response to lithium treatment

It is unable to find support for the involvement of variation in IMPA2 in susceptibility to bipolar disorder, but the role of this and other genes from the phosphoinositol signalling pathway in predicting response to lithium treatment merits further investigation.

C18orf1 located on chromosome 18p11.2 may confer susceptibility to schizophrenia.

The pericentromeric region of chromosome 18, especially 18p11.2, is described as a schizophrenia susceptibility locus. We had previously cloned two novel brain-derived transcripts from this region:

Spatial Expression Patterns and Biochemical Properties Distinguish a Second myo-Inositol Monophosphatase IMPA2 from IMPA1*

Data suggest that IMPA2 has a separate function in vivo from that of IMPA1, which is predicted to have lithium-inhibitable IMPase activity based on its homology to IMPA0 and which was inhibited at high lithium and restricted magnesium concentrations.



An integrated physical map of 18p11.2: a susceptibility region for bipolar disorder

To facilitate positional cloning of a susceptibility gene, a combination of mapping reagents was used to construct a high resolution physical map of the region including sequence tag sites (STSs) and expressed sequence tags (ESTs), which will be an important tool in providing loci for contig construction and positional candidates for mutation screening.

Isolation of chromosome 18-specific brain transcripts as positional candidates for bipolar disorder.

The majority of the transcripts were found to cluster to discrete locations on 18p and 18q, previously hypothesized as susceptibility regions for bipolar disorder, identifying them as positional candidate genes.

Evidence for linkage of bipolar disorder to chromosome 18 with a parent-of-origin effect.

The results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder.

Mechanism of inositol monophosphatase, the putative target of lithium therapy.

Model, kinetic, and mutagenesis studies on the enzyme reveal the requirement for two metal ions in the catalytic mechanism, and a two-metal mechanism is reported, consistent with the reduced catalytic activity observed with substrate analogues lacking the 6-OH.

Linkage analyses of chromosome 18 markers do not identify a major susceptibility locus for bipolar affective disorder in the Old Order Amish.

If a susceptibility locus for bipolar disorder is located in this region of chromosome 18, it is of minor significance in this population of Old Order Amish families.

cDNA cloning of human and rat brain myo-inositol monophosphatase. Expression and characterization of the human recombinant enzyme.

Using probes derived from the bovine inositol monophosphatase cDNA, isolated cDNA clones encoding the human and rat brain enzymes are isolated and their biochemical properties are examined.

Probing the role of metal ions in the mechanism of inositol monophosphatase by site-directed mutagenesis.

From the recently solved crystal structure of the human enzyme, several amino acid residues in the active site were targeted for mutagenesis studies and resulted in parallel reductions in both lithium and magnesium affinity, suggesting that Li+ and Mg2+ share a common binding site.

A Gene Map of the Human Genome

The gene map unifies the existing genetic and physical maps with the nucleotide and protein sequence databases in a fashion that should speed the discovery of genes underlying inherited human disease.