Publications and Links

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia

Molecular Psychiatry, advance online publication 20 March 2007.

T Lencz1, 2, 3, T V Morgan4, M Athanasiou5, B Dain5, C R Reed5, J M Kane1, 2, 3, R Kucherlapati4, 6 and A K Malhotra1, 2, 3
1. 1Department of Psychiatry Research, The Zucker Hillside Hospital, Division of the North Shore–Long Island Jewish Health System, Glen Oaks, NY, USA
2. 2The Feinstein Institute for Medical Research, Manhasset, NY, USA
3. 3Department of Psychiatry and Behavioral Science, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, USA
4. 4Partners HealthCare Center for Personalized Genetic Medicine, Cambridge, MA, USA
5. 5PGxHealth, a Division of Clinical Data, Inc., New Haven, CT, USA
6. 6Department of Genetics, Harvard Medical School, Boston, MA, USA
Schizophrenia is a strongly heritable disorder, and identification of potential candidate genes has accelerated in recent years. Genomewide scans have identified multiple large linkage regions across the genome, with fine-mapping studies and other investigations of biologically plausible targets demonstrating several promising candidate genes of modest effect. The recent introduction of technological platforms for whole-genome association (WGA) studies can provide an opportunity to rapidly identify novel targets, although no WGA studies have been reported in the psychiatric literature to date. We report results of a case–control WGA study in schizophrenia, examining 500 000 markers, which revealed a strong effect (P=3.7 10-7) of a novel locus (rs4129148) near the CSF2RA (colony stimulating factor, receptor 2 alpha) gene in the pseudoautosomal region. Sequencing of CSF2RA and its neighbor, IL3RA (interleukin 3 receptor alpha) in an independent case–control cohort revealed both common intronic haplotypes and several novel, rare missense variants associated with schizophrenia. The presence of cytokine receptor abnormalities in schizophrenia may help explain prior epidemiologic data relating the risk for this illness to altered rates of autoimmune disorders, prenatal infection and familial leukemia.

Correspondence: Dr T Lencz, Department of Psychiatry Research, The Zucker Hillside Hospital, 75-59 263rd Street, Glen Oaks, NY 11004, USA. E-mail: lencz@lij.edu

 

NPAS1 Regulates Branching Morphogenesis in Embryonic Lung.

Am J Respir Cell Mol Biol. 2007 Apr;36(4):427-34. Epub 2006 Nov 16.

Levesque BM, Zhou S, Shan L, Johnston P, Kong Y, Degan S, Sunday ME.

Department of Pediatrics, and Department of Pathology, Children's Hospital and Harvard Medical School, Boston, Massachusetts; and Department of Pathology, Duke University Medical Center, Durham, North Carolina

Drosophila trachealess (Trl), master regulator of tracheogenesis, has no known functional mammalian homolog. We hypothesized that genes similar to trachealess regulate lung development. Quantitative(Q) RT-PCR and immunostaining were used to determine spatial and temporal patterns of npas1 gene expression in developing murine lung. Immunostaining for -smooth muscle actin demonstrated myofibroblasts, and protein gene product (PGP)9.5 identified neuroendocrine cells. Branching morphogenesis of embryonic lung buds was analyzed in the presence of antisense or sense oligodeoxynucleotides (ODN). Microarray analyses were performed to screen for changes in gene expression in antisense-treated lungs. QRT-PCR was used to validate the altered expression of key genes identified on the microarrays. We demonstrate that npas1 is expressed in murine embryonic lung. npas1 mRNA peaks early at Embryonic Day (E)10.5–E11.5, then drops to low levels. Sequencing verifies the identity of npas1 transcripts in embryonic lung. NPAS1 immunostaining occurs in nuclei of parabronchial mesenchymal cells, especially at the tracheal bifurcation. Arnt, the murine homolog of Tango (the heterodimerization partner for Trl) is also expressed in developing lung but at constant levels. npas1- or arnt-antisense ODN inhibit lung branching morphogenesis, with altered myofibroblast development and increased pulmonary neuroendocrine cells. On microarrays, we identify > 50 known genes down-regulated by npas1-antisense, including multiple genes regulating cell migration and cell differentiation. QRT-PCR confirms significantly decreased expression of the neurogenic genes RBP-Jk and Tle, and three genes involved in muscle development: –ig-h3, claudin-11, and myocardin. Npas1 can regulate myofibroblast distribution, branching morphogenesis, and neuroendocrine cell differentiation in murine embryonic lung.

PMID: 17110583 [PubMed - as supplied by publisher]

Correspondence and requests for reprints should be addressed to Mary E. Sunday, M.D., Ph.D., Department of Pathology, Duke University Medical Center, Research Drive, Carl Building, Room 0043, Durham, NC 27710. E-mail: mary.sunday@duke.edu.

 

Gene expression changes in peripheral blood cells provide insight into the biological mechanisms associated with regimen-related toxicities in patients being treated for head and neck cancers.

Oncol. 2006 Aug 18; [Epub ahead of print]

Sonis S, Haddad R, Posner M, Watkins B, Fey E, Morgan TV, Mookanamparambil L, Ramoni M.

Division of Oral Medicine and Head and Neck Cancer, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, MA, USA.

Patients treated with radiotherapy are prone to a constellation of local and systemic toxicities including mucositis, xerostomia, fatigue and anorexia. The biological complexities and similarities underlying the development of toxicities have recently been realized. Mucosal barrier injury is one of the best studied, and gene expression patterns, based on animal tissue samples, have added to its understanding. While investigations gene expression based on tissue samples was valuable, its use precludes more generalizable conclusions relative to common pathogenic mechanisms. Additionally, attempting to define the kinetics of changes in gene expression by sequential sampling is pragmatically unrealistic. Our objectives were: 1. to determine if changes in gene expression could be detected during toxicity development using PBM from patients receiving chemoradiation; 2. to characterize the relationship of expressed genes using graph theory and pathway analysis; and 3. to evaluate potential relationships between the expression of particular genes, canonical pathways, and functional networks in explaining the pathogenesis of regimen-related toxicities.DESIGN: Microarray analysis was performed using PBM-derived cRNA obtained before and 2 weeks after the initiation of chemoradiation in five patients with head and neck cancer who developed documented regimen-related toxicities. We created a database of those genes newly expressed at 2 weeks and evaluated their potential significance relative to toxicity, by canonical pathway analysis, compilation of regional networks around focus genes, and development of a model globalizing the individual functional networks. There was strong concordance between known pathogenic mechanisms of toxicity and the genes, pathways, and networks developed by our data. A role was elicited for unsuspected genes in toxicity development. Our results support the concept that radiation induced toxicities have common underlying mechanisms and demonstrate the utility of PBM as an RNA source for genetic studies. This methodology could be broadly applicable to the study of regimen-related toxicities.

PMID: 16920386 [PubMed - as supplied by publisher]

 

Expression of acute-phase response proteins in retinal Muller cells in diabetes.

Invest Ophthalmol Vis Sci. 2005 Jan;46(1):349-57.

Gerhardinger C, Costa MB, Coulombe MC, Toth I, Hoehn T, Grosu P.

Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114, USA. chiara@vision.eri.harvard.edu

PURPOSE: To characterize the whole spectrum of gene expression changes induced by diabetes in retinal Muller glial cells. METHODS: Muller cells were isolated from the retina of streptozotocin-diabetic and age-matched control rats by gradient centrifugation and immediately processed for RNA isolation. The gene expression profile of Muller cells was studied with the GeneChip Rat Genome oligonucleotide array (Affymetrix, Santa Clara, CA). The upregulation of acute-phase proteins in the retina of diabetic rats was confirmed by Northern and Western blot analyses. Real-time-RT-PCR was used to study the retinal expression of inflammatory cytokines. RESULTS: Gene expression profiling identified 78 genes as differentially expressed in diabetic Muller cells. One third of these genes were associated with inflammation, including a large cluster (18% of the differentially expressed genes) of acute-phase response proteins: alpha2-macroglobulin, ceruloplasmin, complement components, lipocalin-2, metallothionein, serine protease inhibitor-2, transferrin, tissue inhibitor of metalloproteases-1, transthyretin, and the transcription factor C/EBPdelta. Northern and Western blot analyses confirmed the upregulation of alpha2-macroglobulin and ceruloplasmin in the diabetic retina, but not in the cerebral cortex and liver of the same animals. The acute-phase response of Muller cells in diabetes was associated with upregulation of interleukin (IL)-1beta in the retina. CONCLUSIONS: Muller cells acquire a complex and specific reactive phenotype in diabetes characterized by the induction of acute-phase response proteins and other inflammation-related genes. The concomitant upregulation of IL-1beta in the retina of diabetic rats points to this cytokine as a possible mediator of the acute-phase response mounted by Muller cells in diabetes.

PMID: 15623795 [PubMed - indexed for MEDLINE]