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Open Access 01-12-2013 | Research

Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome

Authors: Nicholas G Campbell, Chong-Bin Zhu, Kathryn M Lindler, Brian L Yaspan, Emily Kistner-Griffin, William A Hewlett, Christopher G Tate, Randy D Blakely, James S Sutcliffe, NIH ARRA Consortium

Published in: Molecular Autism | Issue 1/2013

Abstract

Background

Rare genetic variation is an important class of autism spectrum disorder (ASD) risk factors and can implicate biological networks for investigation. Altered serotonin (5-HT) signaling has been implicated in ASD, and we and others have discovered multiple, rare, ASD-associated variants in the 5-HT transporter (SERT) gene leading to elevated 5-HT re-uptake and perturbed regulation. We hypothesized that loci encoding SERT regulators harbor variants that impact SERT function and/or regulation and therefore could contribute to ASD risk. The adenosine A3 receptor (A3AR) regulates SERT via protein kinase G (PKG) and other signaling pathways leading to enhanced SERT surface expression and catalytic activity.

Methods

To test our hypothesis, we asked whether rare variants in the A3AR gene (ADORA3) were increased in ASD cases vs. controls. Discovery sequencing in a case-control sample and subsequent analysis of comparison exome sequence data were conducted. We evaluated the functional impact of two variants from the discovery sample on A3AR signaling and SERT activity.

Results

Sequencing discovery showed an increase of rare coding variants in cases vs. controls (P=0.013). While comparison exome sequence data did not show a significant enrichment (P=0.071), combined analysis strengthened evidence for association (P=0.0025). Two variants discovered in ASD cases (Leu90Val and Val171Ile) lie in or near the ligand-binding pocket, and Leu90Val was enriched individually in cases (P=0.040). In vitro analysis of cells expressing Val90-A3AR revealed elevated basal cGMP levels compared with the wildtype receptor. Additionally, a specific A3AR agonist increased cGMP levels across the full time course studied in Val90-A3AR cells, compared to wildtype receptor. In Val90-A3AR/SERT co-transfections, agonist stimulation elevated SERT activity over the wildtype receptor with delayed 5-HT uptake activity recovery. In contrast, Ile171-A3AR was unable to support agonist stimulation of SERT. Although both Val90 and Ile171 were present in greater numbers in these ASD cases, segregation analysis in families showed incomplete penetrance, consistent with other rare ASD risk alleles.

Conclusions

Our results validate the hypothesis that the SERT regulatory network harbors rare, functional variants that impact SERT activity and regulation in ASD, and encourages further investigation of this network for other variation that may impact ASD risk.

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Title: Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome
Authors: Nicholas G Campbell
Chong-Bin Zhu
Kathryn M Lindler
Brian L Yaspan
Emily Kistner-Griffin
William A Hewlett
Christopher G Tate
Randy D Blakely
James S Sutcliffe
NIH ARRA Consortium
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: Molecular Autism / Issue 1/2013
Electronic ISSN: 2040-2392
DOI: https://doi.org/10.1186/2040-2392-4-28

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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