(Taken from the application): Critical functions for epidermal gap junctions have been elucidated by the discovery of mutations in human connexin genes underlying palmoplantar keratodoma (PPK) and erythrokeratodermia variabilis (EKV). Mutations in the connexin26 (Cx26, or GJB2) gene are not only a major cause of nonsyndromic deafness, but can also cause syndromic forms of hearing loss that are associated with mutilating keratoderma (i.e. Vohwinkel's syndrome). In a similar fashion, mutations in Cx31 (GJB3) can cause either hearing loss, or EKV. Currently, it is not clear how two very distinct pathologies can arise from different mutations within the same connexin gene, which seems to be the case for both Cx31 and Cx26. There is evidence to suggest that simple loss of function mutations in Cx26 cause deafness, but not PPK. Thus, the Cx26 mutations which can cause both PPK and deafness must show some type of alteration of function, and the mechanisms whereby Cx26 mutation leads to pathological changes in the epidermis remains to be elucidated. Thus far, nothing is known about the functional consequences of Cx31 mutations. The objective of this application is to precisely define the functional consequences of Cx26 and Cx31 mutations that cause skin disease in humans. In addition, we seek to understand which keratinocyte functions require gap junctional communication in vivo. To achieve these goals, we first propose to analyze wildtype and mutant Cx26 and Cx31 channel behavior in the paired Xenopus oocyte assay. We will also analyze the ability of the Cx26 mutants to interact with other epidermally expressed connexins in a dominant manner. In a second specific aim, we will attempt to generate and characterize transgenic mice expressing the mutant alleles in keratinocytes in order to evaluate the in vitro derived functional differences in animal models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
7R21AR047102-02
Application #
6447941
Study Section
Special Emphasis Panel (ZAR1-AAA-A (M1))
Program Officer
Moshell, Alan N
Project Start
2000-08-10
Project End
2002-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$75,250
Indirect Cost
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
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White, Thomas W (2003) Nonredundant gap junction functions. News Physiol Sci 18:95-9
White, Thomas W; Srinivas, Miduturu; Ripps, Harris et al. (2002) Virtual cloning, functional expression, and gating analysis of human connexin31.9. Am J Physiol Cell Physiol 283:C960-70
Rouan, F; White, T W; Brown, N et al. (2001) trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. J Cell Sci 114:2105-13
Bruzzone, R; Gomes, D; Denoyelle, E et al. (2001) Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness. Cell Commun Adhes 8:425-31