The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome.
Mutations in the GJB2 gene (Cx26) cause deafness in humans. Most are loss-of-function mutations and cause nonsyndromic deafness. Some mutations produce a gain of function and cause syndromic deafness associated with skin disorders, such as keratitis-ichthyosis-deafness syndrome (KIDS). Cx26-G45E is a lethal mutation linked to KIDS that forms constitutively active connexin hemichannels. The pathomechanism(s) by which mutant Cx26 hemichannels perturb normal epidermal cornification are poorly understood. We created an animal model for KIDS by generating an inducible transgenic mouse expressing Cx26-G45E in keratinocytes. Cx26-G45E mice displayed reduced viability, hyperkeratosis, scaling, skin folds, and hair loss. Histopathology included hyperplasia, acanthosis, papillomatosis, increased cell size, and osteal plugging. These abnormalities correlated with human KIDS pathology and were associated with increased hemichannel currents in transgenic keratinocytes. 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.
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA.
Gulistan
G
Mese
Caterina
C
Sellitto
Leping
L
Li
Hong-Zhan
HZ
Wang
Virginijus
V
Valiunas
Gabriele
G
Richard
Peter R
PR
Brink
Thomas W
TW
White
D019943:Amino Acid Substitution; D000818:Animals; D000072259:Connexin 26; D017630:Connexins / Q000096:biosynthesis* / Q000235:genetics; D003638:Deafness / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D007057:Ichthyosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D007634:Keratitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense
D017630:Connexins; C000607042:GJB2 protein, human; C000607043:Gjb2 protein, mouse; D000072259:Connexin 26