Genomes and Genes
The Role of Connexin32 in the Pathogenesis of CMTX
Principal Investigator: STEVEN SIMON SCHERER
Affiliation: University of Pennsylvania
Abstract: DESCRIPTION (provided by the applicant): Connexin 32 (Cx32) belongs to a gene family of at least 15 members (in mammals), all of which encode gap junction proteins. Six connexins oligomerize to form a hemi-channel (or connexon), which forms a channel when apposed to another hemi-channel on an adjacent membrane. Gap junctions allow the diffusion of ions and small molecules, typically with a molecular mass less than 1000 Da. Individual hemichannels can be composed of more than one connexin (heterotypic connexons), and hemichannels composed of different connexins can also form channels (heterotypic gap junctions). In a series of papers, my colleagues and I have investigated how mutations in the human Cx32 gene cause the X-linked form of Charcot-Marie-Tooth disease (CMTX). This is the second most common form of inherited demyelinating neuropathy (CMT type 1), a genetically heterogenous group that collectively is among the most common inherited neurological diseases. We were the first to show that mutations cause CMTX, that Cx32 is localized to incisures and paranodes (regions of the Schwann cell (SC) myelin sheath that are composed on non-compact myelin) and that the SC myelin sheath contains functional gap junctions. Of particular relevance to this grant, some mutations result in loss of the protein, or alter trafficking so that the mutant protein does not reach the cell membrane. Of the mutants that reach the cell membrane, some fail to form functional gap junctions (communication-incompetent), whereas others are communication-competent. We have made transgenic mice that express wild type or two different mutant Cx32 alleles and found that trafficking of the two mutant proteins was similar to that in transfected cells. One of the mutants, Arg142Trp, has a dominant-negative effect on wild type Cx32: not only does the mutant protein "hang up" in the Golgi, it also causes the wild type protein to accumulate there, too. The goals of this competing renewal are as follows: (1) to determine whether the effects of CMTX mutations are autonomous to myelinating Schwann cells; (2) to determine how Cx32 mutants that form gap junctions in vitro disrupt the function of myelinating SC; (3) to determine whether myelinating SC express other connexins and whether other connnexins can substitute for Cx32 in myelinating SC. The results will elucidate how gap junction proteins are assembled and function in myelinating SC, provide fundamental information on the molecular pathophysiology of CMTX, and illuminate how mutations in other gap junction proteins cause disease.
Funding Period: 2001-12-15 - 2006-11-30
more information: NIH RePORT
- Altered ion channels in an animal model of Charcot-Marie-Tooth disease type IAJérôme J Devaux
Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 6077, USA
J Neurosci 25:1470-80. 2005..Thus, the profound reorganization of axonal ion channels and the aberrant expression of novel ion channels likely contribute to the altered conduction in Trembler-J nerves...
- Cx29 and Cx32, two connexins expressed by myelinating glia, do not interact and are functionally distinctMeejin Ahn
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6077, USA
J Neurosci Res 86:992-1006. 2008..Substituting the intracellular loop and/or tail of Cx32 with those of Cx29 appears to prevent Cx32 from forming functional gap junctions...
- Human connexin26 and connexin30 form functional heteromeric and heterotypic channelsSabrina W Yum
Section of Neurology, St Christopher s Hospital For Children, Erie Ave at Front St, Philadelphia, PA 19134, USA
Am J Physiol Cell Physiol 293:C1032-48. 2007..These results indicate that Cx26 and Cx30 form functional heteromeric and heterotypic channels, whose biophysical properties and permeabilities are different from their homotypic counterparts...
- Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like diseaseJennifer L Orthmann-Murphy
Department of Neurology, University of Pennsylvania School of Medicine, Room 464 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA 19104 6077, USA
Mol Cell Neurosci 34:629-41. 2007..Thus, the Cx47 mutants associated with PMLD likely disrupt the gap junction coupling between astrocytes and oligodendrocytes...
- Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activityDaniela M Menichella
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
J Neurosci 26:10984-91. 2006..1 function in a common pathway. Together, these results implicate oligodendrocytes and their connexins as having critical roles in the buffering of K+ released during neuronal activity...
- Pannexin1 is expressed by neurons and glia but does not form functional gap junctionsYan Huang
Department of Neurology, The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 6077, USA
Glia 55:46-56. 2007..Thus, at least in these mammalian cells lines, Panx1 does not form morphological or functional gap junctions, and it remains to be demonstrated that Panx1 forms gap junction-forming protein in the CNS...
- The effects of a dominant connexin32 mutant in myelinating Schwann cellsLinda Jo Bone Jeng
Cell and Molecular Biology Graduate Group, The University of Pennsylvania Medical Center, Philadelphia, PA 19104 6077, USA
Mol Cell Neurosci 32:283-98. 2006..Thus, the R142W mutant protein has dominant effects that are distinct from overexpression...
- Prenylation-defective human connexin32 mutants are normally localized and function equivalently to wild-type connexin32 in myelinating Schwann cellsYan Huang
Department of Neurology, The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA
J Neurosci 25:7111-20. 2005..These results indicate that Cx32 is prenylated, but that prenylation is not required for proper trafficking of Cx32 and perhaps not even for certain aspects of its function, in myelinating Schwann cells...
- Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null miceSteven S Scherer
Department of Neurology and Cell and Molecular Biology Graduate Group, The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 6077, USA
J Neurosci 25:1550-9. 2005..These results indicate that the loss of Schwann-cell-autonomous expression of Cx32 is sufficient to account for demyelination in CMT1X...
- Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutantsIrene Sargiannidou
Clinical Neurosciences Section, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
Neurobiol Dis 30:221-33. 2008..3. Thus, Cx31.3 shares many characteristics with its ortholog Cx29. Cx32 mutants with CNS phenotypes do not affect the trafficking or function of Cx31.3, and may have other toxic effects in oligodendrocytes...