title: High-throughput screen detects calcium signaling dysfunction in typical sporadic autism spectrum disorder.
abstract: Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders without any defined uniting pathophysiology. Ca2+signaling is emerging as a potential node in the genetic architecture of the disorder. We previously reported decreased inositol trisphosphate (IP3)-mediated Ca2+release from the endoplasmic reticulum in several rare monogenic syndromes highly comorbid with autism - fragile X and tuberous sclerosis types 1 and 2 syndromes. We now extend those findings to a cohort of subjects with sporadic ASD without any known mutations. We developed and applied a high throughput Fluorometric Imaging Plate Reader (FLIPR) assay to monitor agonist-evoked Ca2+signals in human primary skin fibroblasts. Our results indicate that IP3-mediated Ca2+release from the endoplasmic reticulum in response to activation of purinergic receptors is significantly depressed in subjects with sporadic as well as rare syndromic forms of ASD. We propose that deficits in IP3-mediated Ca2+signaling represent a convergent hub function shared across the spectrum of autistic disorders - whether caused by rare highly penetrant mutations or sporadic forms - and holds promise as a biomarker for diagnosis and novel drug discovery.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.|Center for Autism Research and Translation, University of California, Irvine, California, USA.
authors.forename: Galina
authors.initials: G
authors.lastname: Schmunk
authors.affiliation: Center for Autism Research and Translation, University of California, Irvine, California, USA.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Nguyen
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.|Center for Autism Research and Translation, University of California, Irvine, California, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Ferguson
authors.affiliation: Center for Autism Research and Translation, University of California, Irvine, California, USA.
authors.forename: Kenny
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.|Center for Autism Research and Translation, University of California, Irvine, California, USA.|Department of Neurobiology and Behavior, School of Biological Sciences, University of California, Irvine, California, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Parker
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA.|Center for Autism Research and Translation, University of California, Irvine, California, USA.|Division of Human Genetics &Genomics, Department of Pediatrics, School of Medicine, University of California, Irvine, California, USA.
authors.forename: J Jay
authors.initials: JJ
authors.lastname: Gargus
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000378:metabolism* / Q000523:psychology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D057054:Molecular Imaging; D012372:ROC Curve; D059467:Transcriptome; D055815:Young Adult
chemical_list: D000255:Adenosine Triphosphate; D002118:Calcium