title: Shared functional defect in IP₃R-mediated calcium signaling in diverse monogenic autism syndromes.
abstract: Autism spectrum disorder (ASD) affects 2% of children, and is characterized by impaired social and communication skills together with repetitive, stereotypic behavior. The pathophysiology of ASD is complex due to genetic and environmental heterogeneity, complicating the development of therapies and making diagnosis challenging. Growing genetic evidence supports a role of disrupted Ca(2+) signaling in ASD. Here, we report that patient-derived fibroblasts from three monogenic models of ASD-fragile X and tuberous sclerosis TSC1 and TSC2 syndromes-display depressed Ca(2+) release through inositol trisphosphate receptors (IP3Rs). This was apparent in Ca(2+) signals evoked by G protein-coupled receptors and by photoreleased IP3 at the levels of both global and local elementary Ca(2+) events, suggesting fundamental defects in IP3R channel activity in ASD. Given the ubiquitous involvement of IP3R-mediated Ca(2+) signaling in neuronal excitability, synaptic plasticity, gene expression and neurodevelopment, we propose dysregulated IP3R signaling as a nexus where genes altered in ASD converge to exert their deleterious effect. These findings highlight potential pharmaceutical targets, and identify Ca(2+) screening in skin fibroblasts as a promising technique for early detection of individuals susceptible to ASD.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.|Center for Autism Research and Translation, University of California, Irvine, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Schmunk
authors.affiliation: Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Boubion
authors.affiliation: Center for Autism Research and Translation, University of California, Irvine, CA, USA.|Department of Neurobiology and Behavior, School of Biological Sciences, University of California, Irvine, CA, USA.
authors.forename: I F
authors.initials: IF
authors.lastname: Smith
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.|Center for Autism Research and Translation, University of California, Irvine, CA, USA.|Department of Neurobiology and Behavior, School of Biological Sciences, University of California, Irvine, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Parker
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA.|Center for Autism Research and Translation, University of California, Irvine, CA, USA.|Division of Human Genetics & Genomics, Department of Pediatrics, School of Medicine, University of California, Irvine, CA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Gargus
mesh_terms: D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008957:Models, Genetic; D009431:Neural Conduction / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D012879:Skin Physiological Phenomena; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D053496:Inositol 1,4,5-Trisphosphate Receptors; D043562:Receptors, G-Protein-Coupled; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C497683:FMR1 protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human