C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib

Research output: Contribution to journalCase reportContributedpeer-review


  • Friedrich G. Kapp - , University of Freiburg (Author)
  • Stefanie Kretschmer - , Department of Paediatrics (Author)
  • Cora C.A. Beckmann - , University of Freiburg (Author)
  • Lena Wäsch - , University of Freiburg (Author)
  • Anne Molitor - , University of Strasbourg, Hôpital civil (Author)
  • Raphaël Carapito - , University of Strasbourg, Hôpital civil (Author)
  • Mario Schubert - , Institute of Pharmacology and Toxicology (Author)
  • Nadja Lucas - , Department of Paediatrics (Author)
  • Solène Conrad - , Université de Nantes (Author)
  • Sylvaine Poignant - , Université de Nantes (Author)
  • Bertrand Isidor - , Université de Nantes (Author)
  • Meino Rohlfs - , Ludwig Maximilian University of Munich (Author)
  • Ayşenur Paç Kisaarslan - , Erciyes University (Author)
  • Denny Schanze - , Otto von Guericke University Magdeburg (Author)
  • Martin Zenker - , Otto von Guericke University Magdeburg (Author)
  • Annette Schmitt-Graeff - , University of Freiburg (Author)
  • Brigitte Strahm - , University of Freiburg (Author)
  • Anke Peters - , University of Freiburg (Author)
  • Ayami Yoshimi - , University of Freiburg (Author)
  • Wolfgang Driever - , University of Freiburg (Author)
  • Thomas Zillinger - , University of Bonn (Author)
  • Claudia Günther - , Department of Dermatology (Author)
  • Shovamayee Maharana - , Indian Institute of Science Bangalore (Author)
  • Kaomei Guan - , Institute of Pharmacology and Toxicology (Author)
  • Christoph Klein - , Ludwig Maximilian University of Munich (Author)
  • Stephan Ehl - , University of Freiburg (Author)
  • Charlotte M. Niemeyer - , University of Freiburg (Author)
  • Ekrem Unal - , Erciyes University (Author)
  • Seiamak Bahram - , University of Strasbourg, Hôpital civil (Author)
  • Fabian Hauck - , Ludwig Maximilian University of Munich (Author)
  • Min Ae Lee-Kirsch - , Department of Paediatrics (Author)
  • Carsten Speckmann - , University of Freiburg (Author)


C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments. Here, we demonstrate in four NOCARH patients from three families that cell-intrinsic activation of type I interferon (IFN) is a previously unrecognized driver of autoinflammation in NOCARH. Our data show that aberrant innate immune activation is caused by sensing of cytosolic nucleic acids released from mitochondria, which exhibit disturbances in integrity and dynamics due to CDC42 dysfunction. In one of our patients, treatment with the Janus kinase inhibitor ruxolitinib led to complete remission, indicating that inhibition of type I IFN signaling may have an important role in the management of autoinflammation in patients with NOCARH.


Original languageEnglish
Article number109777
JournalClinical immunology
Publication statusPublished - Nov 2023

External IDs

ORCID /0000-0002-8375-8233/work/143958309
ORCID /0000-0002-4330-1861/work/143958616


ASJC Scopus subject areas


  • Autoinflammation, CDC42, JAK inhibition, NOCARH, Ruxolitinib, Type I interferonopathy