Supplementary Material for: Characterization of a Novel Mutation in <b><i>SLC1A1 </i></b>Associated with Schizophrenia

We have recently described a hemi-deletion on chromosome 9p24.2 at the <i>SLC1A1</i> 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 <i>SLC1A1</i> using sequence upstream of exon 2 as a surrogate promoter. However, confocal microscopy and electrophysiological recordings demonstrate that the 5′-truncated <i>SLC1A1</i> 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 <i>SLC1A1</i> or overexpression of full-length or 5′-truncated <i>SLC1A1</i>. Expression changes of several genes strongly implicated in schizophrenia pathophysiology were detected (e.g. <i>SLC1A2</i>,<i> SLC1A3</i>,<i> SLC1A6</i>,<i> SLC7A11</i>,<i> GRIN2A</i>,<i> GRIA1 </i>and<i> DLX1</i>).