Mutations in the BLOC-1 Subunits Dysbindin and Muted Generate Divergent and Dosage-dependent Phenotypes

• Type of Material: Article
• Authors: Jennifer Larimore, Agnes Scott College; Stephanie A. Zlatic, Emory University; Avanti Gokhale, Emory University; Karine Tornieri, Emory University; Kaela S. Singleton, Agnes Scott College; Ariana P. Mullin, Emory University; Junxia Tang, University of Pennsylvania; Konrad Talbot, Cedars-Sinai Medical Center; Victor Faundez, Emory University
• Language: English
• Date: 2014-05-16
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M114.553750
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 289
• Issue: 20
• Start Page: 14291
• End Page: 14300
• Grant/Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grants GM077569 and NS42599 (to V. F.), R01 MH072880 and PP MH064045 (to K. T.), and Emory University Integrated Cellular Imaging Microscopy Core and Viral Cores of the Emory Neuroscience NINDS Core Facilities Grant P30NS055077.; S.A.Z. was supported by Graduate and Postdoctoral Training in Toxicology Training Grant T32 1P50NS071669 from the NIEHS, National Institutes of Health.; This work was also supported by funds from the Children's Hospital of Atlanta (CHOA) Children's Center for Neuroscience (to V. F.).
• Keywords: SCHIZOPHRENIA SUSCEPTIBILITY GENE; BRAIN-DYSFUNCTION; HERMANSKY-PUDLAK-SYNDROME; MUTANT MICE; MOUSE MODEL; WORKING-MEMORY; LYSOSOME-RELATED ORGANELLES; Schizophrenia; HEALTHY-INDIVIDUALS; Adaptor Proteins; PROTEIN COMPLEXES; Biochemistry & Molecular Biology; Science & Technology; Protein Complexes; Synapses; Mouse Genetics; Life Sciences & Biomedicine; SNAPIN
• Research Categories: Biology, Cell; Chemistry, Biochemistry; Health Sciences, Pathology

Abstract

Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5mu/mu) and dysbindin (Bloc1s8sdy/sdy). Transcripts of NMDAreceptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5mu/mu and Bloc1s8 sdy/sdy mice. Unlike Bloc1s8sdy/sdy, elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders.