A genotype-first approach reveals the molecular basis of pyrin inflammasome activation.

Authors

Naoya Iwata, Yoshihiko Kuchitsu, Atsushi Hijikata, Hirofumi Shibata, Masahiko Nishitani-Isa, Mariko Aoki, Kazushi Izawa, Hiroyuki Yoshitomi, Junko Takita, Hideki Ueno, Tomohiko Taguchi, Takahiro Yasumi, Yoshitaka Honda

Published in

Science immunology. Volume 11. Issue 122. Pages eaea0705. Aug 07, 2026. Epub Aug 07, 2026.

Abstract

Mutations in the MEFV gene, which encodes pyrin, are associated with a spectrum of inflammatory conditions called pyrin-associated autoinflammatory diseases (PAADs). Of the 400 MEFV variants listed in the Infevers database, most are classified as variants of uncertain significance. Thus, genetic diagnosis of PAADs remains challenging, and the molecular mechanisms underlying pyrin activation remain poorly understood. Here, we used a cell-based pyroptosis assay to stratify 265 missense MEFV variants and identified previously uncharacterized pathogenic variants. We then characterized the interaction between the pyrin B30.2 domain and CDC42, a key regulator of pyrin intracellular trafficking and activation. We found that classical familial Mediterranean fever (FMF)-related variants bind tightly to CDC42 to induce pyrin hyperactivation, whereas certain non-FMF variants induce pyrin hyperactivation independently of CDC42, indicating involvement of multiple pathways in pyrin activation. Our approach provides a proof of concept for a genotype-first approach, which may advance our understanding of complex human diseases.

PMID:
42566500
Bibliographic data and abstract were imported from PubMed on 08 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.