Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients

Megumu Saito, Ryuta Nishikomori, Naotomo Kambe, Akihiro Fujisawa, Hideaki Tanizaki, Kyoko Takeichi, Tomoyuki Imagawa, Tomoko Iehara, Hidetoshi Takada, Tadashi Matsubayashi, Hiroshi Tanaka, Hisashi Kawashima, Kiyoshi Kawakami, Shinji Kagami, Ikuo Okafuji, Takakazu Yoshioka, Souichi Adachi, Toshio Heike, Yoshiki Miyachi, Tatsutoshi Nakahata

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100 Citations (Scopus)


Cryopyrin-associated periodic syndrome (CAPS) is a spectrum of systemic autoinflammatory disorders in which the majority of patients have mutations in the cold-induced autoinflammatory syndrome (CIAS)1 gene. Despite having indistinguishable clinical features, some patients lack CIAS1 mutations by conventional nucleotide sequencing. We recently reported a CAPS patient with mosaicism of mutant CIAS1, and raised the possibility that CIAS1 mutations were overlooked in "mutation-negative" patients, due to a low frequency of mosaicism. To determine whether there were latent mutant cells in "mutation-negative" patients, we sought to identify mutation-associated biologic phenotypes of patients' monocytes. We found that lipopolysaccharide selectively induced necrosis-like cell death in monocytes bearing CIAS1 mutations. Monocyte death correlated with CIAS1 up-regulation, was dependent on cathepsin B, and was independent of caspase-1. Cell death was intrinsic to CIAS1-mutated monocytes, was not mediated by the inflammatory milieu, and was independent of disease severity or anti-IL-1 therapy. By collecting dying monocytes after lipopolysaccharide treatment, we succeeded in enriching CIAS1-mutant monocytes and identifying low-level CIAS1-mosaicism in 3 of 4 "mutationnegative" CAPS patients. Our findings reveal a novel effect of CIAS1 mutations in promoting necrosis-like cell death, and demonstrate that CIAS1 mosaicism plays an important role in mutation-negative CAPS patients.

Original languageEnglish
Pages (from-to)2132-2141
Number of pages10
Issue number4
Publication statusPublished - Feb 15 2008


All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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