Deafness and Skin Disease

Mutations in the human gene encoding connexin26 (Cx26, or GJB2) cause either nonsyndromic deafness, or syndromic hearing loss associated with skin diseases. The finding that distinct clinical disorders can be caused by different mutations within the same gene suggests that different channel activities influence the ear and skin. Since nonsyndromic deafness linked to Cx26 is predominantly a loss of function disorder, it has been proposed that syndromic Cx26 mutations must show an alteration, or gain, of function to cause skin disease. This idea has been supported by studies of connexin mutations linked to skin disorders such as keratitis-ichthyosis-deafness (KID) syndrome. KID syndrome is a rare disorder characterized by vascularizing keratitis, deafness, hair follicle defects, and erythrokeratoderma. KID patients have recurrent cutaneous infections that lead to lethal septicemia in severe cases. Some connexins can form functional hemichannels in addition to gap junction channels, suggesting that some disease linked mutations may result in abnormal hemichannel activity, and we have found that increased hemichannel activity is a common feature of the human Cx26 mutations responsible for KID syndrome. 

CX26 MUTATIONS LIKED TO KID SYNDROME HAVE INCREASED HEMICHANNEL ACTIVITY

The KID mutation Cx26-A88V induced large hemichannel currents in Xenopus oocytes. Cells were subjected to voltage pulses while membrane currents were recorded. H2O injected cells displayed negligible currents. The KID mutation displayed much larger currents than wild-type Cx26. Western blotting showed that wild-type and mutant connexins were equally expressed.

The majority of Cx26 mutations linked to KIDS have been shown to display increased hemichannel activity. The availability of a mouse model that faithfully recapitulates skin disease will facilitate future studies to explore the relationship between increased hemichannel activity and epidermal homeostasis, with the ultimate goal of developing new therapies to treat this human disorder.

Related Publications:

C. Peres, C. Sellitto, C. Nardin, S. Putti, T. Orsini, F. Scavizzi, M. Raspa, F. Zonta, G. Yang, T.W. White and F. Mammano (2023). Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice.  eBioMedicine 89:104453 C. Peres, C. Sellitto, C. Nardin, S. Putti, T. Orsini, F. Scavizzi, M. Raspa, F. Zonta, G. Yang, T.W. White and F. Mammano (2023). Antibody gene transfer treatment drastically improves epidermal pathology in a keratitis ichthyosis deafness syndrome model using male mice.  eBioMedicine 89:104453 

C. Sellitto, L. Li and T.W. White (2021). Connexin hemichannel inhibition ameliorates epidermal pathology in a mouse model of keratitis ichthyosis deafness syndrome. Sci. Rep. 11:24118 R. Bruzzone and T.W. White (2020). Connexin hemichannel inhibition improves skin pathology in Clouston syndrome mice.  EBioMedicine 57:102856

M.Y. Lee, H.-Z. Wang, T.W. White, T. Brooks, A. Pittman, H. Halai, A. Petrova, D. Xu, S. Hart, V.A. Kinsler, and W.-L. Di (2020). Allele-specific small interfering RNA corrects aberrant cellular phenotype in keratitis-ichthyosis-deafness syndrome keratinocytes. J. Invest. Derm. 140:1035-1044

M. Srinivas, T.F. Jannace, A.G. Cocozzelli, L. Li, N. Slavi, C. Sellitto, T.W. White (2019). Connexin43 mutations linked to skin disease have augmented hemichannel activity Sci. Rep. 9:19

L. Youssefian, H. Vahidnezhad, A.H. Saeidian, H. Mahmoudi, R. Karamzadeh, A. Kariminejad, J. Huang, L. Li, T.F. Jannace, P. Fortina, S. Zeinali, T.W. White, J. Uitto (2019). A novel autosomal recessive GJB2-associated disorder: Ichthyosis follicularis, bilateral severe sensorineural hearing loss and palmoplantar keratoderma. Hum. Mutat. 40:217-229

M. Delmar, D.W. Laird, C.C. Naus, M.S. Nielsen, V.K. Verselis and T.W. White (2018). Connexins and disease. Cold Spring Harb. Perspect. Biol. 10:a029348

Z. Shuja, L. Li, S. Gupta, G. Meşe, and T.W. White (2016). Connexin26 mutations causing palmoplantar keratoderma and deafness interact with connexin43, modifying gap junction and hemichannel properties. J. Invest. Derm. 136:225-235

N.A. Levit, C. Sellitto, H.-Z. Wang, L. Li, M. Srinivas, P.R. Brink, and T.W. White (2015). Aberrant connexin26 hemichannels underlying keratitis-ichthyosis-deafness syndrome are potently inhibited by mefloquine. J. Invest. Derm. 135:1033-1042

P.V. Mhaske, N.A. Levit, L. Li, H.-Z. Wang, J.R. Lee, Z. Shuja, P.R. Brink, and T.W. White (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–C1158

N.A. Levit, G. Meşe, M.-G. R. Basaly and T.W. White (2012). Pathological hemichannels associated with human Cx26 mutations causing Keratitis-Ichthyosis-Deafness syndrome. Biochim. Biophys. Acta 1818:2014-2019

G. Meşe, C. Sellitto, L. Li, H.-Z. Wang, V. Valiunas, G. Richard, P.R. Brink and T.W. White (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 22:4776-4786

H.A. Sánchez, G. Meşe, M. Srinivas, T.W. White and V.K. Verselis (2010). Differentially altered Ca2+ regulation and Ca2+permeability in Cx26 hemichannels formed by the A40V and G45E mutations that cause Keratitis-Ichthiosis-Deafness Syndrome. J. Gen. Physiol. 136:47-62

M. Tekin, X.-J. Xia, R. Erdenetungalag, F.B. Cengiz, T.W. White, J. Radnaabazar, B. Dangaasuren, H. Tastan, W.E. Nance, A. Pandya (2010). GJB2 mutations in Mongolia: Complex alleles, low frequency, and reduced fitness of the deaf. Ann. Hum. Genet. 74:155-164

J.R. Lee, A.M. DeRosa and T.W. White (2009). Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes. J. Invest. Derm. 129:870-878

G. Meşe, V. Valiunas, P.R. Brink and T.W. White (2008). Connexin26 deafness associated mutations show altered permeability to large cationic molecules. Am. J. Physiol. Cell Physiol. 295:C966–C974

D.A. Gerido, A.M. DeRosa, G. Richard and T.W. White (2007). Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness. Am. J. Physiol. Cell Physiol. 293:C337-C345

G. Meşe, E. Londin, R. Mui, P.R. Brink and T.W. White (2004). Altered gating properties of functional Cx26 mutants associated with recessive non-syndromic hearing loss. Hum. Genet. 115:191-199

J.R. Montgomery, T.W. White, B.L. Martin, M.L. Turner and S.M. Holland (2004). A novel connexin 26 gene mutation associated with features of the keratitis-ichthyosis-deafness syndrome and the follicular occlusion triad. J. Am. Acad. Dermatol. 51:377-382

R. Bruzzone, V. Veronesi, D. Gomès, M. Bicego, N. Duval, S. Marlin, C. Petit, P. D'Andrea and T.W. White (2003). Loss of function and residual channel activity of connexin26 mutations associated with nonsyndromic deafness. FEBS Letters 533:79-88

R. Bruzzone, D. Gomès, F. Denoyelle, N. Duval, J. Perea, V. Veronesi, D. Weil, C. Petit, M-M. Gabellec, P. D'Andrea and T.W. White (2001). Functional analysis of a dominant mutation of human connexin26 associated with nonsyndromic deafness. Cell Commun. Adhes. 8:425-431

F. Rouan, T.W. White, N. Brown, A.M. Taylor, T.W. Lucke, D.L. Paul, C. Munro, J. Uitto, M. Hodgins and G. Richard (2001). Trans-dominant inhibition of connexin-43 by mutant connexin-26: implications for dominant connexin disorders affecting epidermal differentiation. J. Cell Sci. 114:2105-2113

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G. Richard, T.W. White, L.E. Smith, R.A. Bailey, J.G. Compton, D.L. Paul and S. Bale (1998). Functional defects of Cx26 resulting from a heterozygous missense mutation in a family with dominant deaf-mutism and palmoplantar keratoderma. Hum. Genet. 103:393-399