title: Characterization of a Novel Mutation in SLC1A1 Associated with Schizophrenia.
abstract: We have recently described a hemi-deletion on chromosome 9p24.2 at the SLC1A1 gene locus and its co-segregation with schizophrenia in an extended Palauan pedigree. This finding represents a point of convergence for several pathophysiological models of schizophrenia. The present report sought to characterize the biological consequences of this hemi-deletion. Dual luciferase assays demonstrated that the partially deleted allele (lacking exon 1 and the native promoter) can drive expression of a 5'-truncated SLC1A1 using sequence upstream of exon 2 as a surrogate promoter. However, confocal microscopy and electrophysiological recordings demonstrate that the 5'-truncated SLC1A1 lacks normal membrane localization and glutamate transport ability. To identify downstream consequences of the hemi-deletion, we first used a themed qRT-PCR array to compare expression of 84 GABA and glutamate genes in RNA from peripheral blood leukocytes in deletion carriers (n = 11) versus noncarriers (n = 8) as well as deletion carriers with psychosis (n = 5) versus those without (n = 3). Then, targeted RNA-Seq (TREx) was used to quantify expression of 375 genes associated with neuropsychiatric disorders in HEK293 cells subjected to either knockdown of SLC1A1 or overexpression of full-length or 5'-truncated SLC1A1. Expression changes of several genes strongly implicated in schizophrenia pathophysiology were detected (e.g. SLC1A2, SLC1A3, SLC1A6, SLC7A11, GRIN2A, GRIA1 and DLX1).
authors.affiliation: Departments of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y., USA.
authors.forename: Parisa
authors.initials: P
authors.lastname: Afshari
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, N.Y., USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Myles-Worsley
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, N.Y., USA.
authors.forename: Ori S
authors.initials: OS
authors.lastname: Cohen
authors.affiliation: Palau Ministry of Health, Ngerulmud, Republic of Palau.
authors.forename: Josepha
authors.initials: J
authors.lastname: Tiobech
authors.affiliation: Departments of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y., USA; Departments of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, N.Y., USA.
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.affiliation: Department of Psychiatry, University of California at San Francisco, San Francisco, Calif., USA.
authors.forename: William
authors.initials: W
authors.lastname: Byerley
authors.affiliation: Departments of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y., USA; Departments of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, N.Y., USA; Departments of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, N.Y., USA.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Middleton
keywords: Copy number variation; EAAT3 protein; Glutamate; Hemi-deletion; Palau; Psychosis; RNA-Seq; Real-time PCR