Pathogenesis of connexin 47 associated diseases
Principal Investigator: Charles K Abrams
Abstract: DESCRIPTION (provided by applicant): The connexins are integral membrane proteins that form gap junction channels. However, recent data suggest that connexins may have roles in: 1) regulation of cell growth and proliferation;2) resistance to both apoptotic and necrotic cell death;and 3) regulation of transcription, which are independent of functional channel formation. Mutations in human connexin 47 (CX47) lead to either Pelizaeus Merzbacher Like Disease (PMLD), a severe disorder, or a milder Hereditary Spastic Paraparesis (HSP) phenotype. However, neither the cellular mechanisms by which these mutations cause human disease nor the bases for their differing effects are well understood. Because both PMLD and HSP mutants are predicted to be incompetent to form a functioning junctional pathway, we propose that the greater severity of disease caused by PMLD mutations is not based on loss of junctional coupling. Rather, we hypothesize that the difference is related to a mechanism independent of functional channel formation. We propose to use Illumina Beadchip technology to evaluate and compare the patterns of gene expression produced when WT CX47 or PMLD/HSP mutants are expressed in oligodendrocytes in primary culture obtained from the Cx47 knockout mice. This will allow for the identification of cellular pathways disrupted when disease causing CX47 mutants are expressed in oligodendrocytes lacking CX47WT. We will pay particular attention to transcriptional sequelae of activation of the UPR or disorganization of the junctional complex. The experiments proposed here should provide an understanding of 1) the pathogenesis of PMLD and HSP;and 2) the basis for the differences between these two disorders. Though not the primary goals of this proposal, these studies may also provide insight into the roles of Cx47WT in oligodendrocytes and mechanisms of pathogenesis of human diseases caused by mutations in other connexins. PUBLIC HEALTH RELEVANCE: Connexins are gap junction proteins which provide for intercellular communication, but may have other roles as well. This proposal studies the effects of mutations in a connexin gene which lead to disease of the central nervous system. These studies should lead to a better general understanding of how mutations in connexin genes lead to human disease.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT
- Gap junctions in inherited human disorders of the central nervous systemCharles K Abrams
Department of Neurology and Physiology and Pharmacology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
Biochim Biophys Acta 1818:2030-47. 2012..Recessive GJA1 mutations cause Hallermann-Streiff syndrome, a disorder showing substantial overlap with ODDD. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and functions...