Curing genetic skin disease through altered replication stress response

Abstract

Revertant mosaicism, or "natural gene therapy", refers to the spontaneous in vivo reversion of an inherited mutation in a somatic cell. Only ~50 human genetic disorders exhibit revertant mosaicism, implicating a distinctive role played by mutant proteins in somatic correction of a pathogenic germline mutation. However, the process by which mutant proteins induce somatic genetic reversion in these diseases remains unknown. Here we show that heterozygous pathogenic CARD14 mutations causing autoinflammatory skin diseases, including psoriasis and pityriasis rubra pilaris, are repaired mainly via homologous recombination. Rather than altering the DNA damage response to exogenous stimuli such as X-irradiation or etoposide treatment, mutant CARD14 increased DNA double-strand breaks under conditions of replication stress. Furthermore, mutant CARD14 suppressed new origin firings without promoting crossover events in the replication stress state. Together, these results suggest that mutant CARD14 alters the replication stress response and preferentially drives break-induced replication (BIR), which is generally suppressed in eukaryotes. Our results highlight the involvement of BIR in reversion events, thus revealing a previously undescribed role of BIR that could potentially be exploited to develop therapeutics for currently intractable genetic diseases.

HomozygousCARD14variant presenting as infantile erythroderma

“…Recently, a wild-type CARD14 was detected in the epidermis from healthy skin spots of two unrelated erythrodermic patients, an elderly male, and a young female, harbouring different CARD14 variants. This phenomenon of revertant mosaicism was attributed to the loss of heterozygosity through mitotic homologous recombination 19. A better understanding of this ‘natural gene therapy’ might help us manipulate it for therapeutic benefits in the future.…”