The Role of Connexin32 in the Pathogenesis of CMTX

Summary

Principal Investigator: STEVEN SIMON SCHERER
Affiliation: University of Pennsylvania
Country: USA
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

Top Publications

  1. ncbi Altered ion channels in an animal model of Charcot-Marie-Tooth disease type IA
    Jérôme J Devaux
    Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 6077, USA
    J Neurosci 25:1470-80. 2005
  2. pmc Cx29 and Cx32, two connexins expressed by myelinating glia, do not interact and are functionally distinct
    Meejin Ahn
    Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 6077, USA
    J Neurosci Res 86:992-1006. 2008
  3. ncbi Human connexin26 and connexin30 form functional heteromeric and heterotypic channels
    Sabrina 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
  4. pmc Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease
    Jennifer 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
  5. ncbi Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity
    Daniela M Menichella
    Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Neurosci 26:10984-91. 2006
  6. ncbi Pannexin1 is expressed by neurons and glia but does not form functional gap junctions
    Yan Huang
    Department of Neurology, The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104 6077, USA
    Glia 55:46-56. 2007
  7. ncbi The effects of a dominant connexin32 mutant in myelinating Schwann cells
    Linda 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
  8. ncbi Prenylation-defective human connexin32 mutants are normally localized and function equivalently to wild-type connexin32 in myelinating Schwann cells
    Yan Huang
    Department of Neurology, The University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA
    J Neurosci 25:7111-20. 2005
  9. ncbi Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null mice
    Steven 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
  10. pmc Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutants
    Irene Sargiannidou
    Clinical Neurosciences Section, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
    Neurobiol Dis 30:221-33. 2008

Scientific Experts

  • Jérôme J Devaux
  • Yan Huang
  • Jennifer L Orthmann-Murphy
  • Sabrina W Yum
  • Steven S Scherer
  • Meejin Ahn
  • Linda Jo Bone Jeng
  • Irene Sargiannidou
  • David L Paul
  • Daniela M Menichella
  • Kenneth H Fischbeck
  • Albee Messing
  • Alan Enriquez
  • Jonathan Lee
  • Alejandro Peinado
  • Eric Lancaster
  • Andreas Gustafsson
  • Kleopas A Kleopa
  • Charles K Abrams
  • Richard Reynolds
  • Philip G Haydon
  • Alan D Enriquez
  • Charles Abrams
  • Jai Yoon Sul
  • Erich Sirkowski
  • Rita J Balice-Gordon
  • Rajeshwar Awatramani
  • Marta Majdan
  • Daniel A Goodenough
  • Klaus Willecke
  • Yi Tian Xu

Detail Information

Publications10

  1. ncbi Altered ion channels in an animal model of Charcot-Marie-Tooth disease type IA
    Jérôme 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...
  2. pmc Cx29 and Cx32, two connexins expressed by myelinating glia, do not interact and are functionally distinct
    Meejin 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...
  3. ncbi Human connexin26 and connexin30 form functional heteromeric and heterotypic channels
    Sabrina 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...
  4. pmc Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease
    Jennifer 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...
  5. ncbi Genetic and physiological evidence that oligodendrocyte gap junctions contribute to spatial buffering of potassium released during neuronal activity
    Daniela 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...
  6. ncbi Pannexin1 is expressed by neurons and glia but does not form functional gap junctions
    Yan 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...
  7. ncbi The effects of a dominant connexin32 mutant in myelinating Schwann cells
    Linda 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...
  8. ncbi Prenylation-defective human connexin32 mutants are normally localized and function equivalently to wild-type connexin32 in myelinating Schwann cells
    Yan 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...
  9. ncbi Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null mice
    Steven 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...
  10. pmc Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutants
    Irene 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...