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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01027

Non-functional trace amine-associated receptor 1 (TAAR1) variants in patients with mental disorders

 Grazia Rutigliano1, 2*,  Julia Bräunig3, Claudia Del Grande4, Vittoria Carnicelli5,  Isabella Masci4, Sergio Merlino4,  Gunnar Kleinau6, Luca Tessieri1, Simone Pardossi1,  Sarah Paisdzior3,  Liliana Dell'Osso4,  Heike Biebermann3 and  Riccardo Zucchi5
  • 1Sant'Anna School of Advanced Studies, Italy
  • 2Institute of Clinical Physiology, Italian National Research Council, Italy
  • 3Institut für Experimentelle Pädiatrische Endokrinologie, Charité - Universitätsmedizin Berlin, Germany
  • 4Department of Clinical and Experimental Medicine, University of Pisa, Italy
  • 5Department of Surgical, Medical, Molecular and Critical Pathology, University of Pisa, Italy
  • 6Institute of Medical Physics and Biophysics, Charité Universitätsmedizin Berlin, Germany

Background: The G protein-coupled receptor (GPCR) trace amine-associated receptor 1 (TAAR1) is expressed across brain areas involved in emotions, reward and cognition, and modulates monoaminergic and glutamatergic neurotransmission. TAAR1 is stimulated with nanomolar affinity by 3-iodothyronamine (T1AM), an endogenous messenger considered a novel branch of thyroid hormone signaling. The human gene for TAAR1 maps to locus 6q23, within a region associated with major mental disorders.
Materials and methods: We screened a cohort of patients with major mental disorders (n=104) and a group of healthy controls (n=130) for TAAR1 variants. HEK293 cells were transiently transfected with: i) wild-type TAAR1; ii) mutated TAAR1, either in homozygous or heterozygous state. Cell surface expression and Gs/adenylyl cyclase activation upon administration of β-phenylethylamine (PEA), T1AM, and RO5166017, were assessed.
Results: We detected 13 missense variants in TAAR1 coding region, with a significant enrichment in patients as compared to healthy controls (11 vs 1, 1 variant in both groups, p < 0.01). In silico analysis identified 4 dysfunctional variants, all in patients. Three of these – R23C, Y131C, C263R – were functionally characterized. In cells co-transfected with wild-type and mutated TAAR1 we observed a significant reduction of cell surface expression. In heterozygosity, the 3 TAAR1 variants substantially dampened Gs signaling in response to PEA, and, more robustly, to T1AM. Co-stimulation with PEA and RO5166017 did not yield any improvement in Gs signaling. R23C, Y131C, and C263R are rare in the general population and map in functionally important highly conserved positions across TAAR1 orthologous and paralogous genes.
Conclusions: Our findings suggest that disruptions of TAAR1 activity may be relevant to the pathophysiology of mental disorders, thereby providing a promising target for novel psychopharmacological interventions.

Keywords: Trace amine associated receptor 1, Major mental disorders, single-nucleotide variants, 3-Iodothyronamine (T1AM), Gs/adenylyl cyclase activation, tridimensional homology model

Received: 17 Jun 2019; Accepted: 12 Aug 2019.

Copyright: © 2019 Rutigliano, Bräunig, Del Grande, Carnicelli, Masci, Merlino, Kleinau, Tessieri, Pardossi, Paisdzior, Dell'Osso, Biebermann and Zucchi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Grazia Rutigliano, Sant'Anna School of Advanced Studies, Pisa, Italy,