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The DPYSL2 gene connects mTOR and schizophrenia

X Pham1,2, G Song3, S Lao4

  • 1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Translational Psychiatry
|November 2, 2016
PubMed

Insights

The DPYSL2 gene

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • A polymorphic CT di-nucleotide repeat (DNR) in the 5'-untranslated region (UTR) of the DPYSL2 gene is associated with schizophrenia.
  • This DNR exhibits allelic differences in response to mammalian target of Rapamycin (mTOR) signaling.

Purpose of the Study:

  • To investigate the functional impact of the DPYSL2 DNR and its interaction with mTOR signaling in the context of schizophrenia.
  • To explore the downstream molecular effects of the schizophrenia risk variant of the DPYSL2 DNR.

Main Methods:

  • Microarray analysis to identify protein interactions with DNR alleles.
  • Electrophoretic mobility shift assays to confirm protein binding.
  • CRISPR/Cas9 gene editing to introduce the schizophrenia risk variant (13DNR).
  • RNA sequencing (RNA-seq) to analyze transcriptome changes in edited cells.

Main Results:

  • Differential interaction of DNR alleles with mTOR-related proteins, including HuD/ELAVL4.
  • CRISPR/Cas9-edited cells with the 13DNR variant showed reduced CRMP2 isoform levels and twofold shorter cellular projections.
  • RNA-seq revealed significant transcriptome alterations in edited cells, enriched in immunity-related genes.
  • These gene expression changes showed overlap with ZNF804A targets and reversed signatures of antipsychotic drug treatment.

Conclusions:

  • The DPYSL2 DNR is functionally important and plays a role in schizophrenia pathogenesis.
  • mTOR signaling is implicated in the molecular mechanisms underlying schizophrenia through its interaction with the DPYSL2 DNR.

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