The role of epidermal keratinocytes (KC) in the innate immunity against pathogens has not been proven in human, aside from several lines of evidence in vitro. Cutaneous Candidiasis is limited to intertriginous area in immune-competent individuals. In absence of systemic immune-deficiency, however, patients with keratitis-ichthyosis-deafness (KID) syndrome caused by mutations in GJB2 coding a gap-junction protein Connexin (Cx) 26 develop chronic cutaneous Candidiasis (CCC) in extremities or trunk. A patient with KID syndrome harboring a germline heterozygous mutation in GJB2 (p.D50N) developed numerous patches of apparently normal skin only after the remission of CCC. We collected 5 revertant patches and separated the epidermis. Exome sequencing identified an additional mutation in GJB2 in each sample. These five mutations were independent to each other, suggesting emergence of independent clones harboring additional mutations in GJB2. All of the four mutations that were phase-able were in cis with D50N. Given that D50N causes hyperactivation of Cx26, these mutations are likely to dampen the effect of D50N in KC. The appearance of revertant patches indicates the impaired survival of KC with D50N in CCC, compared to revertant KC. Since revertant KC are predicted to be similar to wild type KC in the channel function of Cx26, KC with D50N can also be suspected to have impaired survival ability in CCC than wild type KC. Thus, we hypothesized that CCC in KID syndrome is based on the vulnerability of KC with germline mutations to Candida sp. We are currently addressing this hypothesis by analyzing the in vitro survival of KC with different genotypes of GJB2 under the presence of Candida sp. and establishing an in vivo model of CCC using inducible KID mouse model using K14-CreERT mice. In conclusion, we suspected the impaired survival of KC against Candida sp. in KID syndrome through the analysis of revertant patches. The presented case might be the first human phenotype showing the role of wild type KC in the resistance against Candida sp. in unaffected individuals.

ESDR197 - Revertant mosaicism as a clue for the role of keratinocytes in innate immunity against Candida species

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING