Sophia Gaynor and Xue Xiao will Present their Research on Thursday, 12/10/15
A Targeted Sequencing Study of Glutamatergic Candidate Genes in Attempted Suicide
Suicidal behavior has been shown to have a heritable component that is partly driven by psychiatric disorders. However, there is also an independent factor contributing to the heritability of suicidality. We previously conducted a whole exome sequencing study of bipolar suicide attempters and bipolar non-attempters to assess this independent factor. This whole exome study implicated glutamatergic neurotransmission in attempted suicide, as did our genome-wide association study (GWAS) of the attempted suicide phenotype. In the current study, we have conducted a targeted next-generation sequencing study of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, neurexin, and neuroligin gene families in 476 bipolar suicide attempters and 473 bipolar non-attempters. The goal of this study was to gather sequence information from coding and regulatory regions of these glutamatergic genes to identify variants associated with attempted suicide. We identified 186 coding variants and 4,298 regulatory variants predicted to be functional in these genes. No individual variants were overrepresented in cases or controls to a degree that was statistically significant after correction for multiple testing. Additionally, none of the gene-level results were statistically significant following correction. While this study provides no direct support for a role of the examined glutamatergic candidate genes, further sequencing in expanded gene sets will be required to understand the role of glutamatergic signaling in the risk for suicidal behavior.
Soluble CR1 Gene therapy rescues renal phenotypes in a murine model of C3G
Xue Xiao1,2, Yuzhou Zhang1, Janice Staber3, Sanjeev Sethi5, Paul B. McCray, Jr.2,3,
Carla M. Nester1,3,4, Richard JH Smith1,2,3,4
1Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, Iowa, USA; 2Interdepartmental PhD Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; 3, 4Departments of Pediatrics and Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA; 5Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
C3 glomerulopathy (C3G) encompasses two prototypical diseases, dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Both diseases are characterized by fluid-phase dysregulation of the alternative pathway (AP) of complement that leads to C3 deposition in the renal glomerulus. Unknown disease triggers and lacks of specific treatments lead to end-stage renal failure in 50% of patients. Soluble complement receptor 1 (sCR1) is a soluble form of a membrane bound regulator of complement. Short-term studies show that sCR1 is capable of restoring complement control in a murine model of C3G, the Cfh-/-/huCR1-Tg mouse. However, within days of terminating treatment, complement dysregulation is again evident. In this study, we sought to determine whether continuous presence of sCR1 could provide long-term complement control in the C3G murine model. Using the piggyBac transposon system coupled with hydrodynamic tail vein injection, we delivered a construct of sCR1 (LHR A-C) to the C3G murine model to provide constitutive sCR1 expression in mouse circulation. Animals were followed for 6 months. sCR1 expression was detected by real time PCR and ELISA in mouse liver and circulation respectively in 6 months. C3 levels approximately doubled and clearance of glomerular C3 and C3 fragments deposition was documented by immunofluorescence. Electronic microscopy showed a reduction in dense deposits in injected as compared to control animals. There were no changes by light microscopy. Renal function improvements had been revealed from stabilized 24-hr urine albumin creatinine ratio. In this study, we proved that long-term expression of sCR1 could rescue the renal phenotype in C3G mice and may be a viable treatment for patients with this disease.