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.
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.
Authors: Thomas Gstrein; Andrew Edwards; Anna Přistoupilová; Ines Leca; Martin Breuss; Sandra Pilat-Carotta; Andi H Hansen; Ratna Tripathy; Anna K Traunbauer; Tobias Hochstoeger; Gavril Rosoklija; Marco Repic; Lukas Landler; Viktor Stránecký; Gerhard Dürnberger; Thomas M Keane; Johannes Zuber; David J Adams; Jonathan Flint; Tomas Honzik; Marta Gut; Sergi Beltran; Karl Mechtler; Elliott Sherr; Stanislav Kmoch; Ivo Gut; David A Keays Journal: Nat Neurosci Date: 2018-01-08 Impact factor: 24.884
Authors: Wibke Bechtel; Martin Helmstädter; Jan Balica; Björn Hartleben; Betina Kiefer; Fatima Hrnjic; Christoph Schell; Oliver Kretz; Shuya Liu; Felix Geist; Dontscho Kerjaschki; Gerd Walz; Tobias B Huber Journal: J Am Soc Nephrol Date: 2013-03-14 Impact factor: 10.121
Authors: Jie Li; Xue Li; Emily Liu; Paul Copeland; Oliver Freudenreich; Donald C Goff; David C Henderson; Xueqin Song; Xiaoduo Fan Journal: Schizophr Res Date: 2013-02-21 Impact factor: 4.939
Authors: Xiaoduo Fan; Emily Liu; Oliver Freudenreich; Paul Copeland; Douglas Hayden; Musie Ghebremichael; Bruce Cohen; Dost Ongur; Donald C Goff; David C Henderson Journal: J Clin Psychopharmacol Date: 2013-04 Impact factor: 3.153
Authors: Silvia N Kariuki; Beverly S Franek; Rachel A Mikolaitis; Tammy O Utset; Meenakshi Jolly; Andrew D Skol; Timothy B Niewold Journal: J Biomed Biotechnol Date: 2010-07-04