Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia

Psychiatric Clinic, First Medical Faculty, Charles University, Prague, Czech Republic.
Biological Psychiatry (Impact Factor: 10.26). 06/2004; 55(10):981-8. DOI: 10.1016/j.biopsych.2004.01.014
Source: PubMed


Genes involved in phosphoinositide (PI) lipid metabolism are excellent candidates to consider in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). One is PIK3C3, a member of the phosphatidylinositide 3-kinase family that maps closely to markers on 18q linked to both BD and SZ in a few studies.
The promoter region of PIK3C3 was analyzed for mutations by single-strand conformation polymorphism analysis and sequencing. A case-control association study was conducted to determine the distribution of variant alleles in unrelated patients from three cohorts. Electromobility gel shift assays (EMSA) were performed to assess the functional significance of variants.
Two polymorphisms in complete linked disequilibrium with each other were identified, -432C- > T and a "C" insert at position -86. The -432T allele occurs within an octamer containing an ATTT motif resembling members of the POU family of transcription factors. In each population analyzed, an increase in -432T was found in patients. EMSAs showed that a -432T containing oligonucleotide binds to brain proteins that do not recognize -432C.
A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients.

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    • "Furthermore, a previous study found that IGF-1 and β-NGF produced synergistic effects on neuronal growth via the phosphoinositide 3-kinase (PI3K)-Akt- glycogen synthase kinase-3 (GSK3) pathway (Jones et al., 2003). The PI3K signaling pathway, one of the major intracellular signaling pathways for neurotrophic factors, is associated with the pathophysiology of bipolar disorder and the therapeutic effects of mood stabilizers (Schlecker et al., 2006; Stopkova et al., 2004). Hence, high IGF-1 levels may be the result of disturbed intracellular signaling, such as an over-activated GSK3 pathway that is not appropriately regulated by reciprocal mechanisms. "
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    • "The implication of genetic factors in SZ and bipolar disorder (BD) is now well established (Craddock et al. 2006). Unsurprisingly, associations between PIK3C3 gene variants in SZ and BD have been reported (Stopkova et al. 2004; Duan et al. 2005; Saito et al. 2005). These studies suggested that PIK3C3 is a putative candidate gene for SZ, BP, and other neurodevelopmental diseases. "
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