title: The DPYSL2 gene connects mTOR and schizophrenia.
abstract: We previously reported a schizophrenia-associated polymorphic CT di-nucleotide repeat (DNR) at the 5'-untranslated repeat (UTR) of DPYSL2, which responds to mammalian target of Rapamycin (mTOR) signaling with allelic differences in reporter assays. Now using microarray analysis, we show that the DNR alleles interact differentially with specific proteins, including the mTOR-related protein HuD/ELAVL4. We confirm the differential binding to HuD and other known mTOR effectors by electrophoretic mobility shift assays. We edit HEK293 cells by CRISPR/Cas9 to carry the schizophrenia risk variant (13DNR) and observe a significant reduction of the corresponding CRMP2 isoform. These edited cells confirm the response to mTOR inhibitors and show a twofold shortening of the cellular projections. Transcriptome analysis of these modified cells by RNA-seq shows changes in 12.7% of expressed transcripts at a false discovery rate of 0.05. These transcripts are enriched in immunity-related genes, overlap significantly with those modified by the schizophrenia-associated gene, ZNF804A, and have a reverse expression signature from that seen with antipsychotic drugs. Our results support the functional importance of the DPYSL2 DNR and a role for mTOR signaling in schizophrenia.
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: X
authors: X
authors: Pham
authors: Department of Pharmacology and Molecular Sciences, Baltimore, MD, USA.
authors: G
authors: G
authors: Song
authors: University of Maryland, College Park, MD, USA.
authors: S
authors: S
authors: Lao
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: L
authors: L
authors: Goff
authors: Department of Pharmacology and Molecular Sciences, Baltimore, MD, USA.
authors: H
authors: H
authors: Zhu
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: D
authors: D
authors: Valle
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: D
authors: D
authors: Avramopoulos
mesh_terms: D000483:Alleles; D002460:Cell Line; D018900:Dinucleotide Repeats / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D017423:Sequence Analysis, RNA; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014162:Transfection; D020506:Untranslated Regions
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D020506:Untranslated Regions; C540527:ZNF804A protein, human; C095114:collapsin response mediator protein-2; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases