481 Functional studies on the pathogenic truncating mutations of CYLD

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