Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery.
Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an IL-1-driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3-mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders.
Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
Takayuki
T
Tanaka
Kazutoshi
K
Takahashi
Mayu
M
Yamane
Shota
S
Tomida
Saori
S
Nakamura
Koichi
K
Oshima
Akira
A
Niwa
Ryuta
R
Nishikomori
Naotomo
N
Kambe
Hideki
H
Hara
Masao
M
Mitsuyama
Nobuhiro
N
Morone
John E
JE
Heuser
Takuya
T
Yamamoto
Akira
A
Watanabe
Aiko
A
Sato-Otsubo
Seishi
S
Ogawa
Isao
I
Asaka
Toshio
T
Heike
Shinya
S
Yamanaka
Tatsutoshi
T
Nakahata
Megumu K
MK
Saito
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D056587:Cryopyrin-Associated Periodic Syndromes / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000473:pathology* / Q000502:physiology; D007223:Infant; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008962:Models, Theoretical; D009030:Mosaicism; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
D002352:Carrier Proteins; D050505:Mutant Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human