Cx26 mutations in syndromic deafness linked to skin disease

Summary

Principal Investigator: Thomas W White
Abstract: DESCRIPTION (provided by applicant): Connexins are the subunit proteins of gap junctions, which allow the exchange of ions, second messengers and small metabolites between adjacent cells through intercellular channels. In addition, connexins can form functional hemichannels in non-junctional membranes. Mutations in connexin genes cause a variety of human diseases, including deafness and skin disorders. For example, mutations in connexin26 (Cx26, or GJB2) cause nonsyndromic deafness, or syndromic deafness associated with a variety of skin disorders including palmoplantar keratoderma (PPK), keratitis- ichthyosis-deafness syndrome (KID), and Vohwinkel syndrome (VS). The Cx26 mutations causing skin diseases and deafness are all single amino acid changes, and the mechanism(s) whereby they lead to skin pathology are unknown. Since nonsyndromic deafness is predominantly a loss of function disorder, it follows that the syndromic mutants may show an alteration, or gain, of function to cause skin disease. In this proposal, we seek to precisely define the functional consequences of Cx26 mutations that cause skin disease in humans. In addition, we seek to develop animal models that replicate human skin disorders caused by connexin mutations and use them to explore potential therapeutic intervention strategies. We propose first to examine the functional properties of dominant Cx26 mutations that cause skin disease. Second, we will generate transgenic mouse models of human skin disease and characterize the progression of epidermal pathology. Third, we will use pharmacological inhibition and/or antisense mediated knockdown in transfected cell systems and transgenic animals to inhibit mutant connexin activity. These studies will provided insights into how mutations alter the functional activity of Cx26 leading to skin disease, if these novel functions change epidermal homeostasis in animal models, and whether specific inhibition of the mutant proteins will show promise as a potential therapeutic strategy. PUBLIC HEALTH RELEVANCE: Mutations in connexin genes cause a broad spectrum of human health problems. In the case of Cx26, functional studies have revealed much about deafness causing mutations, but very little is known about the functional consequences of Cx26 mutations that cause skin disease. The proposed studies will show how mutations alter the functional activity of Cx26 leading to skin disease, whether these novel functions cause skin disease in experimental animals, and if specific inhibition of the mutant proteins will show promise as a possible therapeutic strategy.
Funding Period: 2010-04-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome
    Helmuth A Sánchez
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Gen Physiol 136:47-62. 2010
  2. pmc Zebrafish cx30.3: identification and characterization of a gap junction gene highly expressed in the skin
    Liang Tao
    Department of Biological Sciences, University of Manitoba, Winnipeg, Canada
    Dev Dyn 239:2627-36. 2010
  3. pmc Pathological hemichannels associated with human Cx26 mutations causing Keratitis-Ichthyosis-Deafness syndrome
    Noah A Levit
    The Medical Scientist Training Program, Stony Brook University, Stony Brook, NY, USA
    Biochim Biophys Acta 1818:2014-9. 2012
  4. pmc The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome
    Gulistan Mese
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
    Mol Biol Cell 22:4776-86. 2011
  5. pmc The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity
    Pallavi V Mhaske
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
    Am J Physiol Cell Physiol 304:C1150-8. 2013

Research Grants

  1. Regulation/Role of AcylCer in Normal Epidermis and Atopic Dermatitis
    Peter M Elias; Fiscal Year: 2013
  2. STRUCTURAL ANALYSIS OF GAP JUNCTION TRAFFICKING
    Gina E Sosinsky; Fiscal Year: 2013
  3. PHOSPHORYLATION OF GAP JUNCTION PROTEINS
    Paul D Lampe; Fiscal Year: 2013
  4. Cellular Determinants of Ah Receptor Signaling
    Thomas R Sutter; Fiscal Year: 2013
  5. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
  6. Tissue injury and inflammation in MS (P50)
    Bruce D Trapp; Fiscal Year: 2013
  7. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013

Detail Information

Publications5

  1. pmc Differentially altered Ca2+ regulation and Ca2+ permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause keratitis ichthyosis deafness syndrome
    Helmuth A Sánchez
    Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
    J Gen Physiol 136:47-62. 2010
    ..A40V produces leaky hemichannels, whereas G45E provides a route for excessive entry of Ca(2+). These aberrant properties, alone or in combination, can severely compromise cell integrity and lead to increased cell death...
  2. pmc Zebrafish cx30.3: identification and characterization of a gap junction gene highly expressed in the skin
    Liang Tao
    Department of Biological Sciences, University of Manitoba, Winnipeg, Canada
    Dev Dyn 239:2627-36. 2010
    ..Thus, zebrafish could potentially serve as an excellent model to study disorders of the skin and deafness that result from human connexin mutations...
  3. pmc Pathological hemichannels associated with human Cx26 mutations causing Keratitis-Ichthyosis-Deafness syndrome
    Noah A Levit
    The Medical Scientist Training Program, Stony Brook University, Stony Brook, NY, USA
    Biochim Biophys Acta 1818:2014-9. 2012
    ..This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics...
  4. pmc The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome
    Gulistan Mese
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
    Mol Biol Cell 22:4776-86. 2011
    ..These results confirm the pathogenic nature of the G45E mutation and provide a new model for studying the role of aberrant connexin hemichannels in epidermal differentiation and inherited connexin disorders...
  5. pmc The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity
    Pallavi V Mhaske
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
    Am J Physiol Cell Physiol 304:C1150-8. 2013
    ..These results show that these two mutations exhibit a shared gain of functional activity and support the hypothesis that increased hemichannel activity is a common feature of human Cx26 mutations responsible for KID syndrome...

Research Grants30

  1. Regulation/Role of AcylCer in Normal Epidermis and Atopic Dermatitis
    Peter M Elias; Fiscal Year: 2013
    ....
  2. STRUCTURAL ANALYSIS OF GAP JUNCTION TRAFFICKING
    Gina E Sosinsky; Fiscal Year: 2013
    ..We investigate the connexin43 trafficking process using an imaging based approach examining the hierarchy of connexin43 phosphorylation events and where within the cell cycle, connexin43-kinase(s) interactions occurs. ..
  3. PHOSPHORYLATION OF GAP JUNCTION PROTEINS
    Paul D Lampe; Fiscal Year: 2013
    ....
  4. Cellular Determinants of Ah Receptor Signaling
    Thomas R Sutter; Fiscal Year: 2013
    ..The results of these studies will generate the knowledge that is necessary to design minimally invasive studies using small skin biopsies and tape stripping methods in future translational studies of human populations exposed to dioxin. ..
  5. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
  6. Tissue injury and inflammation in MS (P50)
    Bruce D Trapp; Fiscal Year: 2013
    ..abstract_text> ..
  7. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....