887 Truncated pathogenic CYLD variants cause differential cellular events

The skin tumor syndrome, CYLD cutaneous syndrome (CCS) is featured by the development of multiple variable adnexal tumors. CCS develops as a consequence of the pathogenic variants of a tumor suppressor gene, cylindromatosis (CYLD) encoding a deubiquitinase enzyme known as a negative regulator of the NF-κB signaling. Nonsense mutations of the CYLD gene cause the largest phenotypic diversity of the disease and nearly half of them (i.e. 40%) are recurrent. To elucidate the molecular and cellular consequences of three pathogenic variants of the CYLD protein, an in vitro experimental system was used. The recurrent CYLD(Arg936X) and CYLD(Arg758X) truncated derivatives and the novel CYLD(Tyr602X) mutant variant identified by our group in a Hungarian CCS patient were investigated. In silico and in vitro functional analyses were performed to compare the structure, stability and signaling of these truncated CYLD variants. CYLD(Arg936X) had the most profound effect on NF-κB activity. The other two protein variants showed altered stability, the CYLD(Arg758X) being an extremely unstable, while the CYLD(Tyr602X) being the most stable variant, both showing minor effects on NF-κB activity. Our results correlate with the phenotype spectrum caused by the three investigated CYLD mutations. Thus, we conclude that they might contribute to the development of CCS with distinct mechanisms.