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Integrating computational modeling and experimental data to unravel the molecular and intracellular effects of a disease-linked variant of the oxytocin receptor*
- Dr. Mercedes Alfonso-Prieto -
- Research Centre Juelich -
- Juelich, North Rhine Westfalia, Germany -
Abstract
The oxytocin receptor (OXTR) is a GPCR abundantly expressed in the brain involved in the regulation of multiple social and emotional behaviors. Single nucleotide polymorphisms (SNPs) in the OXTR gene have been associated with several psychological traits in genome-wide association studies, including autism spectrum disorder (ASD). For instance, the non-synonymous SNP rs4686302, which causes an A218T change in the OXTR protein, has been associated with deficits in social communication and cognition, restricted and repetitive behaviors, and differences in emotional empathy. Intriguingly, sequence-based predictions of the functional effect of this variant did not identify it as damaging, in contrast to the observed phenotype. Here we have combined in vitro and in silico approaches to analyze the structural, functional, and intracellular effects of the OXTR A218T variant. Structural modeling indicates that the mutant A218T OXTR is more stable than the wild-type, in line with protein degradation assays. In addition, the mutation is predicted to alter the flexibility of transmembrane helix 5, which in turn could affect receptor activation. Integration of this molecular information into a systems biology-based model of the OXTR-mediated signaling cascade resulting in calcium release from the endoplasmic reticulum is able to reproduce calcium imaging data. Subsequent whole-genome and RNA sequencing analyses reveal differentially regulated genes in A218T compared to wild-type OXTR-containing cells, some of which are associated with ASD. Altogether, the integration of computational modeling and experimental data provides the molecular and cellular mechanisms by which the OXTR rs4686302 SNP leads to ASD-associated genetic dysregulations.
About Dr. Mercedes Alfonso-Prieto
Group Leader at the Research Centre Juelich & Assistant Professor at the Heinrich Heine University Duesseldorf
Author list and affiliations
Magdalena Meyer[1], Benjamin Jurek[1,2], Mercedes Alfonso-Prieto[3,4], Rui Ribeiro[5], Vladimir M. Milenkovic[6], Julia Winter[1], Petra Hoffmann[7,8], Christian H. Wetzel[6], Alejandro Giorgetti[3,5], Paolo Carloni[3,9,10], and Inga D. Neumann[1]
[1] Department of Behavioral and Molecular Neurobiology, University of Regensburg, Germany
[2] Department of Molecular and Cellular Anatomy, University of Regensburg, Germany
[3] Institute of Neuroscience and Medicine INM-9, Institute for Advanced Simulations IAS-5, Forschungszentrum Jülich, Germany
[4] Cécile and Oskar Vogt Institute for Brain Research, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Germany
[5] Department of Biotechnology, University of Verona, Italy
[6] Department of Psychiatry and Psychotherapy, University of Regensburg, Germany
[7] Regensburg Center for Interventional Immunology (RCI), Germany
[8] Department of Internal Medicine III, University Hospital Regensburg, Germany
[9] Department of Physics, RWTH Aachen University, Germany
[10] JARA-Institute: Molecular Neuroscience and Neuroimaging, Institute for Neuroscience and Medicine INM-11/JARA-BRAIN Institute JBI-2, Forschungszentrum Jülich GmbH, Germany
Dr. Mercedes Alfonso-Prieto on the web
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