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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059505-03
Application #
8230659
Study Section
Special Emphasis Panel (ZRG1-MOSS-C (02))
Program Officer
Baker, Carl
Project Start
2010-04-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$336,964
Indirect Cost
$110,808
Name
State University New York Stony Brook
Department
Physiology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Lilly, Evelyn; Sellitto, Caterina; Milstone, Leonard M et al. (2016) Connexin channels in congenital skin disorders. Semin Cell Dev Biol 50:4-12
Shuja, Zunaira; Li, Leping; Gupta, Shashank et al. (2016) Connexin26 Mutations Causing Palmoplantar Keratoderma and Deafness Interact with Connexin43, Modifying Gap Junction and Hemichannel Properties. J Invest Dermatol 136:225-35
Levit, Noah A; White, Thomas W (2015) Connexin hemichannels influence genetically determined inflammatory and hyperproliferative skin diseases. Pharmacol Res 99:337-43
Shuja, Zunaira; Li, Leping; Gupta, Shashank et al. (2015) Connexin26 Mutations Causing Palmoplantar Keratoderma and Deafness Interact with connexin43, Modifying Gap Junction and Hemichannel Properties. J Invest Dermatol :
Santa Cruz, Ana; Meşe, Gülistan; Valiuniene, Laima et al. (2015) Altered conductance and permeability of Cx40 mutations associated with atrial fibrillation. J Gen Physiol 146:387-98
Levit, Noah A; Sellitto, Caterina; Wang, Hong-Zhan et al. (2015) Aberrant connexin26 hemichannels underlying keratitis-ichthyosis-deafness syndrome are potently inhibited by mefloquine. J Invest Dermatol 135:1033-42
Mhaske, Pallavi V; Levit, Noah A; Li, Leping et al. (2013) The human Cx26-D50A and Cx26-A88V mutations causing keratitis-ichthyosis-deafness syndrome display increased hemichannel activity. Am J Physiol Cell Physiol 304:C1150-8
Levit, Noah A; Mese, Gulistan; Basaly, Mena-George R et al. (2012) Pathological hemichannels associated with human Cx26 mutations causing Keratitis-Ichthyosis-Deafness syndrome. Biochim Biophys Acta 1818:2014-9
Mese, Gulistan; Sellitto, Caterina; Li, Leping et al. (2011) The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome. Mol Biol Cell 22:4776-86
Tao, Liang; DeRosa, Adam M; White, Thomas W et al. (2010) Zebrafish cx30.3: identification and characterization of a gap junction gene highly expressed in the skin. Dev Dyn 239:2627-36

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