A group of human mutations within the N-terminal (NT) domain of connexin 26 (Cx26) hemichannels produce aberrant channel activity, which gives rise to deafness and skin disorders, including keratitis-ichthyosis-deafness (KID) syndrome.
Furthermore, we revealed that the expressions of IL15, CCL5, IL1A, IL23R and TLR5 are down-regulated in keratinocytes expressing Cx26-D50N, suggesting that immune deficiency in KID syndrome expressing Cx26-D50N might be associated not only with skin barrier defects, but also with the down-regulated expression of immune response-related genes.
Keratitis-ichthyosis-deafness (KID) syndrome is a rare genodermatosis that typically results from mutations of the GJB2 gene or, less commonly, the GJB6 gene.
In 2009 the term porokeratotic anexial ostial nevus was proposed to comprehend porokeratotic eccrine and hair follicle nevus and a related and more common process without follicular involvement: porokeratotic eccrine ostial and dermal duct nevus Recent findings suggest that both entities may be produced by a mutation in GJB2 gene, which is associated to KID syndrome.
These results indicated that GJB2 mutation (p.G12R) in this case of KID syndrome, which was susceptible to T. rubrum infection, might be attributed to a limited native immune response.
Here, we assessed the effect of two Cx26 mutations associated with KID syndrome, Cx26I30N and D50Y, on protein biosynthesis and channel function in N2A and HeLa cells.
There are significant differences in the clinical picture of two rare autosomal dominant syndromes: keratitis-ichthyosis-deafness (KID) syndrome and hidrotic ectodermal dysplasia (Clouston syndrome), which are caused by GJB2 and GJB6 mutations, respectively.
Because in the human skin connexin 26 (Cx26) is co-expressed with other connexins, like Cx43 and Cx30, and as the KID syndrome is inherited as autosomal dominant condition, it is possible that KID mutations change the way Cx26 interacts with other co-expressed connexins.
Pharmacological modulators of Cx26 are needed to assess the pathomechanistic involvement of hemichannels in the development of hyperkeratosis in KID syndrome.
Excessive opening of undocked Cx26 hemichannels in the plasma membrane is associated with disease pathogenesis in keratitis-ichthyosis-deafness (KID) syndrome.
Collectively, these data provide insight into Cx26 structure-function and the underlying bases for the phenotypes associated with KID syndrome patients carrying the D50N mutation.
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.
Several cases of widespread involvement have been reported, including one in association with the keratitis-ichthyosis-deafness (KID) syndrome (OMIM #148210), a rare disorder caused by mutations in the GJB2 gene coding for the gap junction protein connexin26 (Cx26).
Mutations in Connexin26 (Cx26) give rise to a spectrum of dominantly inherited hyperproliferating skin disorders, the severest being keratitis-ichthyosis-deafness (KID) syndrome, an inflammatory skin disorder, with patients prone to opportunistic infections.
Here, we review a proposed role for hemichannels in the pathogenesis of Keratitis-Ichthyosis-Deafness (KID) syndrome associated with connexin26 (Cx26) mutations.