CYLD cutaneous syndrome (CCS) is a rare monogenic skin disease characterized by the development of skin appendage tumors caused by mutations in the cylindromatosis (CYLD) gene. Recently described Hungarian and Anglo-Saxon pedigrees that are affected by CCS carry the same disease-causing truncating mutation of the CYLD gene (Arg936X) but exhibit striking phenotypic differences. Using whole exome sequencing, missense genetic variants of the TRAF3 and NBR1 genes were identified in the affected family members of the Hungarian pedigree that have a more severe phenotype that are not present in the Anglo-Saxon pedigree. Our in vitro functional study revealed that the combined expression of mutant CYLD(Arg936X) with TRAF3 and NBR1 caused increased NF-kB activity, regardless of the presence or absence of mutations in TRAF3 and NBR1. To generalize this we broadened our investigations and included a newly identified (Tyr602X) and already described (Arg758X and Arg936X) disease causing CYLD mutations leading to the formation of premature stop codons causing truncations with different length of the ubiquitin-specific protease (USP) catalytic domain of the CYLD protein. The effect of these nonsense mutations on NF-kB activity in HEK293 cells as a consequence of the dysfunction of the CYLD protein was compared. Contrary to our hypothesis, truncated CYLD protein which lacks the entire USP domain caused no elevated NF-kB activation in our assay as compared to the effect of the overexpression of wt CYLD. We assume that the truncated CYLD proteins have altered characteristics (structure and interaction with partner molecules) that would explain our findings. To improve understanding, we have commenced in silico molecule structure analysis of the truncated proteins.

ESDR481 - Functional studies on the pathogenic truncating mutations of CYLD

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.