WEHI PhD Completion Seminar hosted by Professor Seth Masters

Maria Zyulina

Joint PhD Program Student  - University of Melbourne & University of Bonn, Germany

Masters Group – Hudson Institute at Monash University

Functional analysis of NLRP1 variants of uncertain significance

Online audience

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Meeting ID: 610 2002 2566

Passcode: 990024

NLRP1 is a pattern recognition receptor of the innate immune system that forms inflammatory signalling platforms known as Inflammasomes upon sensing of Pathogen- or Damage-associated molecular patterns. NLRP1 is highly expressed in epithelial tissues like keratinocytes and mucosal tissue and Inflammasome formation ultimately leads to pyroptotic cell death in these tissues.

Certain variants of NLRP1 found in patients have been shown to be responsible for rare inflammatory diseases ranging from generalised systemic inflammation to skin disorders with features such as skin ulcers and keratosis which increases the risk of cancer, and respiratory papillomatosis of the upper airways.

Additional to the pathogenic gain-of-function mutations over 600 other non-synonymous coding variants of NLRP1 were identified in patients. Most have not been thoroughly analysed and thus were classified as variants of uncertain significance (VUS).

In order to systematically assess these variants, we performed functional testing in a HEK293T overexpression model for their spontaneous activation potential and their reaction to known NLRP1 activators. This approach allowed a direct comparison of the variants with the wild-type protein, leading to the identification of 20 previous VUS that are now likely pathogenic. Specific overactive variants were further studied to gain a better understanding of the overall function of the protein.

These functional studies resulting from a high-throughput screening approach will help to improve our overall understanding of NLRP1 inflammasome function and contribute to a more precise classification of NLRP1 associated inflammatory diseases.

All welcome!