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@ARTICLE{Meyer:904805,
      author       = {Meyer, Magdalena and Jurek, Benjamin and Alfonso-Prieto,
                      Mercedes and Ribeiro, Rui and Milenkovic, Vladimir M. and
                      Winter, Julia and Hoffmann, Petra and Wetzel, Christian H.
                      and Giorgetti, Alejandro and Carloni, Paolo and Neumann,
                      Inga D.},
      title        = {{S}tructure-function relationships of the disease-linked
                      {A}218{T} oxytocin receptor variant},
      journal      = {Molecular psychiatry},
      volume       = {27},
      issn         = {1359-4184},
      address      = {London},
      publisher    = {Macmillan},
      reportid     = {FZJ-2022-00135},
      pages        = {907–917},
      year         = {2022},
      note         = {Open Access Article. Open Access funding enabled and
                      organized by Projekt DEAL through University of Regensburg.},
      abstract     = {Various single nucleotide polymorphisms (SNPs) in the
                      oxytocin receptor (OXTR) gene have been associated with
                      behavioral traits, autism spectrum disorder (ASD) and other
                      diseases. The non-synonymous SNP rs4686302 results in the
                      OXTR variant A218T and has been linked to core
                      characteristics of ASD, trait empathy and preterm birth.
                      However, the molecular and intracellular mechanisms
                      underlying those associations are still elusive. Here, we
                      uncovered the molecular and intracellular consequences of
                      this mutation that may affect the psychological or
                      behavioral outcome of oxytocin (OXT)-treatment regimens in
                      clinical studies, and provide a mechanistic explanation for
                      an altered receptor function. We created two monoclonal
                      HEK293 cell lines, stably expressing either the wild-type or
                      A218T OXTR. We detected an increased OXTR protein stability,
                      accompanied by a shift in Ca2+ dynamics and reduced MAPK
                      pathway activation in the A218T cells. Combined whole-genome
                      and RNA sequencing analyses in OXT-treated cells revealed
                      7823 differentially regulated genes in A218T compared to
                      wild-type cells, including 429 genes being associated with
                      ASD. Furthermore, computational modeling provided a
                      molecular basis for the observed change in OXTR stability
                      suggesting that the OXTR mutation affects downstream events
                      by altering receptor activation and signaling, in agreement
                      with our in vitro results. In summary, our study provides
                      the cellular mechanism that links the OXTR rs4686302 SNP
                      with genetic dysregulations associated with aspects of ASD.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524) / 5251 - Multilevel Brain Organization and
                      Variability (POF4-525) / 5252 - Brain Dysfunction and
                      Plasticity (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5241 / G:(DE-HGF)POF4-5251 /
                      G:(DE-HGF)POF4-5252},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34980886},
      UT           = {WOS:000737750600001},
      doi          = {10.1038/s41380-021-01241-8},
      url          = {https://juser.fz-juelich.de/record/904805},
}