Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients.
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 "mutation-negative" 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.
Departments of Pediatrics, Kyoto University Graduate School of Medicine, Shogoin, Sakyo-ku, Kyoto, Japan.
Megumu
M
Saito
Ryuta
R
Nishikomori
Naotomo
N
Kambe
Akihiro
A
Fujisawa
Hideaki
H
Tanizaki
Kyoko
K
Takeichi
Tomoyuki
T
Imagawa
Tomoko
T
Iehara
Hidetoshi
H
Takada
Tadashi
T
Matsubayashi
Hiroshi
H
Tanaka
Hisashi
H
Kawashima
Kiyoshi
K
Kawakami
Shinji
S
Kagami
Ikuo
I
Okafuji
Takakazu
T
Yoshioka
Souichi
S
Adachi
Toshio
T
Heike
Yoshiki
Y
Miyachi
Tatsutoshi
T
Nakahata
D000686:Amyloidosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death; D002869:Chromosome Aberrations; D003638:Deafness / Q000235:genetics; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008581:Meningitis / Q000235:genetics; D009000:Monocytes / Q000473:pathology*; D009030:Mosaicism; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012871:Skin Diseases / Q000235:genetics*; D013577:Syndrome
D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human