TRAF3 and NBR1 both influence the effect of the disease-causing CYLD(Arg936X) mutation on NF-κB activity

Area of Science:

• Genetics
• Molecular Biology
• Cell Signaling

Background:

• CYLD cutaneous syndrome (CCS), also known as Brooke-Spiegler syndrome (BSS), presents with varied phenotypes despite a common CYLD gene mutation (c.2806C>T, p.Arg936X).
• Phenotypic variability suggests the involvement of other genetic factors influencing disease presentation.

Purpose of the Study:

• To investigate the role of TRAF3 and NBR1 genetic variants in modifying the phenotype of CYLD cutaneous syndrome.
• To elucidate the mechanism by which TRAF3 and NBR1 influence the NF-κB signaling pathway in the context of CYLD mutations.

Main Methods:

• Whole exome sequencing to identify genetic variants in affected individuals.
• In vitro experiments using HEK293 cells to assess the impact of wild-type and mutant TRAF3 and NBR1 on CYLD-mediated NF-κB signaling.

Main Results:

• Missense variants in TRAF3 and NBR1 were identified in a Hungarian pedigree with CCS, distinguishing it from an Anglo-Saxon pedigree.
• Combined expression of mutant CYLD(Arg936X) with TRAF3 and NBR1 significantly increased NF-κB activity in HEK293 cells.
• The presence of TRAF3 and NBR1 mutations did not alter the NF-κB activity increase caused by mutant CYLD.

Conclusions:

• Increased expression of TRAF3 and NBR1 potentiates the effect of the CYLD(Arg936X) mutation on NF-κB activity.
• TRAF3 and NBR1 act as phenotype-modifying factors in CYLD cutaneous syndrome.
• Measuring TRAF3 and NBR1 levels could aid in predicting CCS phenotypic differences and patient prognosis.