The p.Lys22AsnGJB2 mutation causes a dominant form of hearing loss associated with variable expression of palmoplantar keratoderma, representing a model of full penetrance, with an age-dependent effect on the phenotype.
These findings suggest a common mechanism whereby Cx26 mutations causing PPK and deafness transdominantly influence multiple functions of wild-type Cx43.
Our findings provide further evidence of a correlation between the p.R75Q mutation in Cx26 and a syndromic hearing impairment with palmoplantar keratoderma.
HeLa cells stably expressing wild type Cx26 were transiently transfected to co-express nine individual dominant Cx26 mutants; six associated with non-syndromic hearing loss (W44C, W44S, R143Q, D179N, R184Q, and C202F) and three associated with hearing loss and palmoplantar keratoderma (G59A, R75Q, and R75W).
To the best of our knowledge, this is the first report of a GJB2 mutation associated with syndromic autosomal dominant hearing loss and palmoplantar keratoderma in a Korean family.
HeLa cells stably expressing nine dominant Cx26 mutants, six associated with non-syndromic hearing loss (W44C, W44S, R143Q, D179N, R184Q and C202F) and three associated with hearing loss and palmoplantar keratoderma (G59A, R75Q and R75W), individually or together with Cx30, were analyzed by immunocytochemistry, co-immunoprecipitation, and functional assays (scrape-loading and/or fluorescence recovery after photobleaching).
Our investigations document additional evidence for the correlation between the cited mutations in the GJB2 gene and a syndromic hearing impairment with palmoplantar keratoderma.
For example, mutations in GJB2, the gene encoding connexin-26 (Cx26), are not only a major cause of nonsyndromic deafness, but also cause syndromic deafness associated with skin disorders such as palmoplantar keratoderma, keratitis-ichthyosis deafness syndrome, Vohwinkel syndrome, hystrix-ichthyosis deafness syndrome and Bart-Pumphrey syndrome.
Mutations in connexin 31 (GJB3) and connexin 30.3 (GJB4), implicated in previous reports of EKV, and connexin 26 (GJB2), implicated in palmoplantar keratoderma, were unlikely given the lack of shared homozygous haplotypes in the regions surrounding these genes.
We have identified the novel G224A (R75Q) mutation in the GJB2 gene in a four-generation family from Turkey with autosomal dominant inherited hearing impairment and PPK.
Dominant mutations of GJB2-encoding connexin-26 (Cx26) have pleiotropic effects, causing either hearing impairment (HI) alone or in association with palmoplantar keratoderma (PPK/HI).
The involvement of GJB2 in autosomal dominant deafness has also been proposed, although the putative mutation identified in one family with both deafness and palmoplantar keratoderma has recently been suggested to be merely a non-disease associated polymorphism.
It has recently been demonstrated that genetic defects in keratin genes cause a number of different skin disorders, including epidermolysis bullosa simplex (EBS), epidermolytic hyperkeratosis (EH), the EH form of epidermal nevi, epidermolytic and non-epidermolytic forms of palmoplantar keratoderma (EPPK and PPK) and pachyonychia congenita (PC).