title: Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors.
abstract: BACKGROUND
  Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA.
  
  
  METHODS
  We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD).
  
  
  RESULTS
  Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis.
  
  
  CONCLUSIONS
  We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD.
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Etienne
authors.initials: E
authors.lastname: Cartier
authors.affiliation: Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States ; Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hamilton
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Belovich
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Aparna
authors.initials: A
authors.lastname: Shekar
authors.affiliation: Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Campbell
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Saunders
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Thorvald F
authors.initials: TF
authors.lastname: Andreassen
authors.affiliation: Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.
authors.forename: Ulrik
authors.initials: U
authors.lastname: Gether
authors.affiliation: Department of Psychiatry and New York State Psychiatric Institute, Columbia University, New York, NY, 10032 USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Veenstra-Vanderweele
authors.affiliation: Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States ; Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center, Dallas TX 75390-8813, United States.
authors.forename: Paula G
authors.initials: PG
authors.lastname: Ulery-Reynolds
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States ; Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Erreger
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States ; Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Heinrich J G
authors.initials: HJ
authors.lastname: Matthies
authors.affiliation: Department of Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States ; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States ; Neuroscience Program in Substance Abuse, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States ; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-8548, United States.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Galli
keywords: Drosophila; autism spectrum disorder; casein kinase 2; dopamine; syntaxin 1; transporter