PMID- 34980886 OWN - NLM STAT- MEDLINE DCOM- 20220503 LR - 20221109 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 27 IP - 2 DP - 2022 Feb TI - Structure-function relationships of the disease-linked A218T oxytocin receptor variant. PG - 907-917 LID - 10.1038/s41380-021-01241-8 [doi] AB - 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 Ca(2+) 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. CI - (c) 2021. The Author(s). FAU - Meyer, Magdalena AU - Meyer M AUID- ORCID: 0000-0002-5388-3850 AD - Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany. FAU - Jurek, Benjamin AU - Jurek B AUID- ORCID: 0000-0001-7124-510X AD - Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany. AD - Department of Molecular and Cellular Anatomy, University of Regensburg, Regensburg, Germany. FAU - Alfonso-Prieto, Mercedes AU - Alfonso-Prieto M AUID- ORCID: 0000-0003-4509-4517 AD - Institute of Neuroscience and Medicine INM-9, Institute for Advanced Simulations IAS-5, Forschungszentrum Julich, Julich, Germany. AD - Cecile and Oskar Vogt Institute for Brain Research, University Hospital Dusseldorf, Medical Faculty, Heinrich Heine University Dusseldorf, Dusseldorf, Germany. FAU - Ribeiro, Rui AU - Ribeiro R AD - Institute of Neuroscience and Medicine INM-9, Institute for Advanced Simulations IAS-5, Forschungszentrum Julich, Julich, Germany. AD - Department of Biotechnology, University of Verona, Verona, Italy. FAU - Milenkovic, Vladimir M AU - Milenkovic VM AD - Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany. FAU - Winter, Julia AU - Winter J AUID- ORCID: 0000-0001-8518-0167 AD - Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany. FAU - Hoffmann, Petra AU - Hoffmann P AD - Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany. AD - Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany. FAU - Wetzel, Christian H AU - Wetzel CH AUID- ORCID: 0000-0002-5762-0003 AD - Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany. FAU - Giorgetti, Alejandro AU - Giorgetti A AD - Institute of Neuroscience and Medicine INM-9, Institute for Advanced Simulations IAS-5, Forschungszentrum Julich, Julich, Germany. AD - Department of Biotechnology, University of Verona, Verona, Italy. FAU - Carloni, Paolo AU - Carloni P AD - Institute of Neuroscience and Medicine INM-9, Institute for Advanced Simulations IAS-5, Forschungszentrum Julich, Julich, Germany. AD - Department of Physics, RWTH Aachen University, Aachen, Germany. AD - JARA-Institute: Molecular Neuroscience and Neuroimaging, Institute for Neuroscience and Medicine INM-11/JARA-BRAIN Institute JBI-2, Forschungszentrum Julich GmbH, Julich, Germany. FAU - Neumann, Inga D AU - Neumann ID AUID- ORCID: 0000-0002-3911-5062 AD - Department of Behavioral and Molecular Neurobiology, University of Regensburg, Regensburg, Germany. inga.neumann@ur.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220104 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (OXTR protein, human) RN - 0 (Receptors, Oxytocin) RN - 50-56-6 (Oxytocin) SB - IM MH - *Autism Spectrum Disorder/drug therapy MH - Female MH - HEK293 Cells MH - Humans MH - Infant, Newborn MH - Oxytocin/metabolism MH - Pregnancy MH - *Premature Birth/drug therapy MH - Receptors, Oxytocin/genetics/metabolism MH - Structure-Activity Relationship PMC - PMC9054668 COIS- The authors declare no competing interests. EDAT- 2022/01/05 06:00 MHDA- 2022/05/04 06:00 PMCR- 2022/01/04 CRDT- 2022/01/04 06:04 PHST- 2021/04/02 00:00 [received] PHST- 2021/07/15 00:00 [accepted] PHST- 2021/06/24 00:00 [revised] PHST- 2022/01/05 06:00 [pubmed] PHST- 2022/05/04 06:00 [medline] PHST- 2022/01/04 06:04 [entrez] PHST- 2022/01/04 00:00 [pmc-release] AID - 10.1038/s41380-021-01241-8 [pii] AID - 1241 [pii] AID - 10.1038/s41380-021-01241-8 [doi] PST - ppublish SO - Mol Psychiatry. 2022 Feb;27(2):907-917. doi: 10.1038/s41380-021-01241-8. Epub 2022 Jan 4.