Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome / Nicholas G. CAMPBELL in Molecular Autism, (August 2013)  

Public ISBD [article]  inMolecular Autism > (August 2013) Titre : Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome Type de document : Texte imprimé et/ou numérique Auteurs : Nicholas G. CAMPBELL, Auteur ; Chong-Bin ZHU, Auteur ; Kathryn LINDLER, Auteur ; Brian YASPAN, Auteur ; Emily KISTNER-GRIFFIN, Auteur ; NIH ARRA CONSORTIUM,, Auteur ; William HEWLETT, Auteur ; Christopher TATE, Auteur ; Randy BLAKELY, Auteur ; James SUTCLIFFE, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : 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. En ligne : http://dx.doi.org/10.1186/2040-2392-4-28 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Rare coding variants of the adenosine A3 receptor are increased in autism: on the trail of the serotonin transporter regulome [Texte imprimé et/ou numérique] / Nicholas G. CAMPBELL, Auteur ; Chong-Bin ZHU, Auteur ; Kathryn LINDLER, Auteur ; Brian YASPAN, Auteur ; Emily KISTNER-GRIFFIN, Auteur ; NIH ARRA CONSORTIUM,, Auteur ; William HEWLETT, Auteur ; Christopher TATE, Auteur ; Randy BLAKELY, Auteur ; James SUTCLIFFE, Auteur. Langues : Anglais (eng) in Molecular Autism > (August 2013) Index. décimale : PER Périodiques Résumé : 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. En ligne : http://dx.doi.org/10.1186/2040-2392-4-28 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Zn2+ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder / Peter J. HAMILTON in Molecular Autism, (February 2015)  

Public ISBD [article]  inMolecular Autism > (February 2015) . - p.1-3 Titre : Zn2+ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Peter J. HAMILTON, Auteur ; Aparna SHEKAR, Auteur ; Andrea N. BELOVICH, Auteur ; Nicole Bibus CHRISTIANSON, Auteur ; Nicholas G. CAMPBELL, Auteur ; James S. SUTCLIFFE, Auteur ; Aurelio GALLI, Auteur ; Heinrich JG MATTHIES, Auteur ; Kevin ERREGER, Auteur Article en page(s) : p.1-3 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Our laboratory recently characterized a novel autism spectrum disorder (ASD)-associated de novo missense mutation in the human dopamine transporter (hDAT) gene SLC6A3 (hDAT T356M). This hDAT variant exhibits dysfunctional forward and reverse transport properties that may contribute to DA dysfunction in ASD. Here, we report that Zn2+ reverses, at least in part, the functional deficits of ASD-associated hDAT variant T356M. These data suggest that the molecular mechanism targeted by Zn2+ to restore partial function in hDAT T356M may be a novel therapeutic target to rescue functional deficits in hDAT variants associated with ASD. En ligne : http://dx.doi.org/10.1186/s13229-015-0002-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277 [article] Zn2+ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder [Texte imprimé et/ou numérique] / Peter J. HAMILTON, Auteur ; Aparna SHEKAR, Auteur ; Andrea N. BELOVICH, Auteur ; Nicole Bibus CHRISTIANSON, Auteur ; Nicholas G. CAMPBELL, Auteur ; James S. SUTCLIFFE, Auteur ; Aurelio GALLI, Auteur ; Heinrich JG MATTHIES, Auteur ; Kevin ERREGER, Auteur . - p.1-3. Langues : Anglais (eng) in Molecular Autism > (February 2015) . - p.1-3 Index. décimale : PER Périodiques Résumé : Our laboratory recently characterized a novel autism spectrum disorder (ASD)-associated de novo missense mutation in the human dopamine transporter (hDAT) gene SLC6A3 (hDAT T356M). This hDAT variant exhibits dysfunctional forward and reverse transport properties that may contribute to DA dysfunction in ASD. Here, we report that Zn2+ reverses, at least in part, the functional deficits of ASD-associated hDAT variant T356M. These data suggest that the molecular mechanism targeted by Zn2+ to restore partial function in hDAT T356M may be a novel therapeutic target to rescue functional deficits in hDAT variants associated with ASD. En ligne : http://dx.doi.org/10.1186/s13229-015-0002-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=277

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