Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia

Pavla Stopkova, Takuya Saito, Demitri F. Papolos, Jan Vevera, Ivo Paclt, Ilja Zukov, Yonina B. Bersson, Benjamin A. Margolis, Rael D. Strous, Herbert M. Lachman

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)981-988
Number of pages8
JournalBiological Psychiatry
Volume55
Issue number10
DOIs
StatePublished - May 15 2004

Fingerprint

POU Domain Factors
Bipolar Disorder
Schizophrenia
Phosphatidylinositols
Alleles
Mutation
Lipid Metabolism
Genetic Promoter Regions
Oligonucleotides
Case-Control Studies
Phosphotransferases
Gels
Brain
Population
Genes
Proteins

Keywords

  • Bipolar disorder
  • Brn
  • inositol phosphates
  • lithium
  • oct-1
  • phosphatidylinositol
  • phosphoinositide
  • POU
  • schizophrenia

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia. / Stopkova, Pavla; Saito, Takuya; Papolos, Demitri F.; Vevera, Jan; Paclt, Ivo; Zukov, Ilja; Bersson, Yonina B.; Margolis, Benjamin A.; Strous, Rael D.; Lachman, Herbert M.

In: Biological Psychiatry, Vol. 55, No. 10, 15.05.2004, p. 981-988.

Research output: Contribution to journalArticle

Stopkova, P, Saito, T, Papolos, DF, Vevera, J, Paclt, I, Zukov, I, Bersson, YB, Margolis, BA, Strous, RD & Lachman, HM 2004, 'Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia', Biological Psychiatry, vol. 55, no. 10, pp. 981-988. https://doi.org/10.1016/j.biopsych.2004.01.014
Stopkova, Pavla ; Saito, Takuya ; Papolos, Demitri F. ; Vevera, Jan ; Paclt, Ivo ; Zukov, Ilja ; Bersson, Yonina B. ; Margolis, Benjamin A. ; Strous, Rael D. ; Lachman, Herbert M. / Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia. In: Biological Psychiatry. 2004 ; Vol. 55, No. 10. pp. 981-988.
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AU - Saito, Takuya

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AU - Vevera, Jan

AU - Paclt, Ivo

AU - Zukov, Ilja

AU - Bersson, Yonina B.

AU - Margolis, Benjamin A.

AU - Strous, Rael D.

AU - Lachman, Herbert M.

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N2 - Background 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. Methods 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. Results 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. Conclusions 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.

AB - Background 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. Methods 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. Results 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. Conclusions 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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