Journal article

Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation

Franklin L Zhong, Ons Mamai, Lorenzo Sborgi, Lobna Boussofara, Richard Hopkins, Kim Robinson, Ildiko Szeverenyi, Takuya Takeichi, Reshmaa Balaji, Aristotle Lau, Hazel Tye, Keya Roy, Carine Bonnard, Patricia J Ahl, Leigh Ann Jones, Paul J Baker, Lukas Lacina, Atsushi Otsuka, Pierre R Fournie, Francois Malecaze Show all

Cell | CELL PRESS | Published : 2016


Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as a..

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University of Melbourne Researchers


Awarded by Great Britain Sasakawa Foundation

Awarded by Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from the Japan Society for the Promotion of Science

Awarded by Grants-in-Aid for Scientific Research

Funding Acknowledgements

We would like to thank all patient family members for their participation in this study. We thank J. Common, D. P. Lunny, Y.Z. Ng, F. Schmidt, J.P.Y. Ting, P. Broz, E. Vigano, X. Bao, and P. Khavari for technical advice. We would like to thank Dr. T. Tebeica for his help with examination of patient pathology. O.M. was a PhD student in the University of Monastir in Tunisia and was funded by an A*STAR Research Attachment Program. The authors acknowledge financial support from the Department of Health via the U.K. National Institute for Health Research Comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust, the Great Britain Sasakawa Foundation no. 4314, Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation (S2404) from the Japan Society for the Promotion of Science, and the Strategic Positioning Fund on Genetic Orphan Diseases from the Biomedical Research Council, A*STAR, Singapore. B.R. is a fellow of the Branco Weiss Foundation and a recipient of the A*STAR Investigatorship. S.H. and B.R. are EMBO Young Investigators.