. 2018 Sep 5;132(17):1901–1924. doi: 10.1042/CS20171498

Table 1. Monogenic autoinflammatory disorder summary table.

Condition	Gene/s	Protein	MOI	GOF/LOF	Pathway	Cytokine group	System involved	Human cell model	Potential murine model	Reference/s
ADAM17 deficiency	ADAM17	ADAM17	AR	LOF	Unknown	Unknown	Skin GIT	PBMC: ↓TNF-α response to LPS, PMA + anti-CD3/anti-CD28 antibodies	Nil	[148]
AGS1	TREX1	TREX1	AR or AD	LOF	IFN	T1IFN	CNS	Human neural stem cell-derived astrocytes, primary astrocytes, brain-derived endothelial cells: shRNA knockdown → IFN gene signature + ↑ proinflammatory cytokines	Trex1^–/– mice	[66,149–151]
AGS2	RNASEH2B	RNASEH2B	AR	LOF	IFN	T1IFN	CNS		Rnaseh2b knockout first [KOF] mice	[68,74]
AGS3	RNASEH2C	RNASEH2C	AR	LOF	IFN	T1IFN	CNS		Rnaseh2c^−/− mice	[68,74,152,153,154]
AGS4	RNASEH2A	RNASEH2A	AR	LOF	IFN	T1IFN	CNS	Human neural stem cell-derived astrocytes, primary astrocytes, brain-derived endothelial cells: shRNA knockdown minimal change in ISG/IFN cytokine profile	Rnaseh2a^G37S/G37S	[68,74,149]
AGS5	SAMHD1	SAMHD1	AR	LOF	IFN	T1IFN	CNS	HeLa cells: transfection of mutant SAMHD1 showed abnormal localisationHuman neural stem cell-derived astrocytes primary astrocytes, brain-derived endothelial cells: shRNA knockdown → IFN gene signature + ↑ proinflammatory cytokines	Samhd1^−/− mice	[67,73,149,155–157]
AGS6	ADAR1	ADAR1	AR	LOF	IFN	T1IFN	CNS	HEK293Tcells: IFN reporter assay Lymphoblastoid cell line: ↓ ADAR1 expression of mutant c/w WTHuman neural stem cell-derived astrocytes, primary astrocytes, brain-derived endothelial cells: shRNA knockdown minimal change in ISG/IFN cytokine profile	Adar^f/− SCL-Cre-ER^T ^* mice	[149,158]
AGS7	IFIH1	MDA5	AD	GOF	IFN	T1IFN	CNS	HEK293T: IFN reporter assay	Ifih1^gs/+ mice	[159–161]
AIADK	NLRP1	NLRP1	AD	GOF	Inflam	IL-18 ?IL-1β	Multiple		Nlrp1a^Q593P mice^*	[162,153]
AIFEC	NLRC4	NLRC4	AD	GOF	Inflam	IL-18	Multiple	Monocytes: ↑IL-1β in response to PrgI Monocyte-derived macrophages: ↑cell death, ↑IL-1β, IL-18 with LPS priming + flagellin HEK293T cells: ASC speck analysis and inflammasome reconstitution iPSCs: ↑IL-1β, IL18 to LPS	mu-NLRC4 transgenic mice	[147,32,163–165]
AILJK	COPA	COPA	AD	Dominant negative	?NF-κB ?IFN		Multiple incl lungs, kidney	CD4 T cells: skewing to Th17 response BLCL: ↓ autophagy, ↑ transcription IL-1 β, IL-6, IL-23 HEK293T cells: siRNA knockdown → ↑ER stress	Nil	[166,167]
APLAID	PLCG2	PLCγ2	AD	GOF	Unknown ?Inflam ?NF-κB	Unknown ?IL-1β	Multiple	PBMC: ↑response to NLRP3 activation B cells: ↑ERK phosphorylation	Multiple^*	[80,82]
Blau syndrome	NOD2	NOD2	AD	GOF	NF-κB	Multiple TNFα	Multiple	HEK293T cells: NF-κB luciferase assay. ↑ activity with transfection of mutants PBMC: single patient w novel variant ↓ NF-κB response	Nod2^2939ic mice	[168–170]
CAPS	NLRP3	NLRP3	AD	GOF	Inflam	IL-1β	Multiple	PBMC: constitutively high IL-1β secretion, as well as IL-6 + TNF THP1 cells: ↑ IL-1β and IL-18 when transduced with mutant c/w WT CD4 T cells: α-CD3 + α-CD46 stimulation →↑ IL-1β in patient cells c/w WT	Nlrp3^A350V^neoR^/+ Nlrp3^L351P^neoR^/+ mice Nlrp3^R258W mice	[21,154,171–173]
Cherubism	SH3BP2	SH3BP2	AD	? GOF ? dominant negative	? NF-κB ? NFATc1	TNF-α	Bone		Sh3bp2 ^P416R^/+ mice	[174,175]
DADA2	CECR1	ADA2	AR	LOF	Unknown	?T1IFN ?TNFα	Multiple incl vascular	PBMC: ↑ B cell death when cultured without stimulation Monocytes: differentiate into M1>M2	Nil	[84,85,92,93]
DIRA	IL1RN	IL-1Ra	AR	LOF	IL-1β	Multiple	Multiple bone	Mononuclear cells: stimulation with IL-1β → ↑ IL-1α, MIP1α, TNFα, IL-8, IL-6 c/w WT	Il1ra⁻^/− mice^*	[176,177,178,179,180,181,40–42]
DITRA	IL36RN	IL-36Ra	AR	LOF	Other	IL-36	Skin	PBMC: IL-36A stimulation → ↑ IL-1α, IL-6, IL-8, TNFα c/w WT	IL1F6 transgenic, IL1F5^−/− mice	[182]
EOIBD	IL10, IL10RA, IL10RB	IL10, IL10RA, IL10RB	AR	LOF	Other	IL-10	GIT	PBMC: Failure of IL-10 to ↓ LPS induced TNF α in patients with receptor mutations; More rapid TNF α response to LPS; Failure to phosphorylate STAT3 in response to IL10	IL10^Trunc/Trunc mice^* IL-10^−/− Cx3cr1^gfp/+ mice	[47,48,51,183]
FCAS2	NLRP12	NLRP12	AD	LOF	NF-κB ? Inflam	TNFα, IL-6, IL-1β	Skin Multiple	HEK293T cells: NF-κB luciferase assay PBMC: ↑ spontaneous TNF-α, IL-6, IL-1β c/w WT	NLRP12^−/− mice	[184–186]
FMF	MEFV	Pyrin	AR>>AD	GOF	Inflam	IL-1β	Multiple	PBMC: no spontaneous IL-1β secretion when cultured. ↑ IL-1β in response to LPS (inconsistent). Anti-CD3/CD28 stimulation → ↑ IL-17 and IL-22 Neutrophils: possible release of IL-1β through NETS	Mefv^M680I/M680I mice Mefv^M694V/M694V mice Mefv^V726A/V726A mice	[178,179,187,188]
H syndrome	SLC29A3	SLC29A3	AR	LOF	Unknown	Unknown	Multiple		ENT3^–/– mice	[189,190]
HA20	TNFAIP3	A20	AR	LOF	NF-κB Inflam		Multiple	HEK293T cells: NF-κB luciferase assay PBMC, fibroblasts: ↑ nuclear translocation p65 at rest + with TNF stimulation PBMC: LPS → ↑ inflammatory cytokines; Polarisation to Th9, Th17 CD4 T cell linage. LPS → NLRP3 inflam activation	A20^−/− mice^*	[14]
HIDS	MVK	MVK	AR	LOF	Inflam	IL-1β	Multiple	PBMC: ↑ IL-1β, IL-6 and TNFα at rest and with stimulation EBV-LCL: accumulation unprenylated Rab proteins (temperature dependent)	Mvk^−/+ mice	[191–195]
HOIL1 deficiency	RBCK1	HOIL1	AR	LOF	NF-κB	Multiple	Multiple	Fibroblasts, B cells: ↓NF-κB activation. JNK phosphorylation normal. Impaired response to IL-1β > TNF CD3+, CD19+, CD56+ cells: No response to TNF or IL-1β stimulation Monocytes: IL-1β stimulation → ↑IL-6 and MIP-1α c/w healthy control	Rbck1^−/− mice^* (overtly normal)	[76]
HOIP deficiency	RNF31	HOIP	AR	LOF	NF-κB	Multiple	Multiple	Fibroblasts: ↓IKK phosphorylation, IL-6 production in response to TNF or IL-1β stimulation B cells: ↓ CD80 up-regulation with CD40L + IL-21 or IL-4 Monocytes: IL-1β stimulation → ↑IL-6 and IL-1β c/w healthy control	Hoip^−/− mice (embryonically lethal). Various crosses	[77]
HYDM1	NLRP7	NLRP7	AR	Unknown	? Inflam ? NF-κB	Unknown	Placenta	HEK293T cells: transient transfection → abnormal methylation PBMC: ↓IL-1β and TNF in response to LPS. Conflicting data on secretion as well as effect on pro-IL-1β expression	Nil (no murine orthologue)	[180,181,196–199]
Majeed syndrome	LPIN2	Lipin 2	AR	LOF	Inflam	IL-1β	Bone Skin Multiple	HEK293T cells: PAP activity assay. Hepa1-6 cells: PPARα luciferase assay.	Lpin2^−/− mice	[200–203]
MSPC	NLRP1	NLRP1	AD	GOF	Inflam	IL-1β	Skin	HEK293T cells: ASC speck assay, reconstitution of inflam ↑pro-IL-1β cleavage Primary keratinocytes: spontaneous inflam activation PMA differentiated THP1 cells: Doxycycline induced NLRP1 expression constructs. Mutants ↑IL-1β and cell death. ASC dependent	Nlrp1a^Q593P mice^*	[153,204]
ORAS	OTULIN	Otulin	AR	LOF	NF-κB	TNF	Multiple	HEK293T cells: transfection of mutant ↑NF-κB pathway c/w WT; NF-κB luciferase assay showed ↓inhibitory effect of mutant Otulin c/w WT T cells: Normal proliferation and NF-κB response to TCR stimulation B cells: Normal proliferation and NF-κB response to BCR stimulation Fibroblasts: Expression undetectable. ↑p-IKBa, p-IKKa/b, p-P38 and P-JNK with TNF stimulation. ↓ ability to deubiquitinate linear chains PBMC: ↓ ability to deubiquitinate linear chains	CreERT2-Otulin^Lac^Z/flox mice	[205,206]
PAAND	MEFV	Pyrin	AD	GOF	Inflam	?Multiple	Skin Multiple	Monocyte: ↑ASC speck formation, caspase-1 activity, c/w healthy control PBMC: ↑ IL-18 and IL-1Ra with LPS stimulation c/w healthy control HEK293T cells: ASC speck assay. 14-3-3 binding in overexpression model THP1 cells: Retroviral reconstitution and lentviral reconstitution of MEFV KO cells. Mutants ↑cell death, ↑IL-1β, IL-18	Nil	[207,208]
PAPA syndrome	PSTPIP1	PSTPIP1	AD	Unknown	Inflam	?IL-1β	Skin, Joints Multiple	HeLa cells: Transient cotransfection. Mutant PSTPIP1 hyperphosphorylated and ↑binding to pyrin Cos-7L cells: inflammasome reconstitution assay. Mutant PSTPIP1 ↑IL-1β processing THP1 cells: Immunoprecipitation to show interaction between PSTPIP1 and pyrin Macrophages: ↓invasion and podosome formation T cells: ↓numbers, ↓proliferation response to mitogen. Normal migration PBMC: ↓ IL-1Ra, ↑IL-1β, IL-6, TNFα and GMCF in response to multiple stimuli. siRNA knockdown of NLRP3 ↓IL-1β in response to LPS	Rosa-PSTPIP1 A230T^{STOP del/+} mice	[209–213]
PLAID	PLCG2	PLCγ2	AD	GOF	Unknown	Unknown	Multiple	COS7, A20 cells: transfection model. Mutants- ↑phospholipase activity at subphysiological temperatures LAD2 mast cells: transfection of mutant → spontaneous degranulation at 20°C B cells and NK cells: ↓ERK phosphorylation in response to stimulation T cells: normal response to CD3 cross-linking	Multiple^*	[79]
PRAAS	PSMB8, PSMB9, PSMB4, PSMA3, POMP	PSMB8, PSMB9, PSMB4, PSMA3, POMP	AR	LOF	?NF-κB ?IFN	T1IFN	Multiple	HeLa cells: Transfection studies show poor formation of proteasome with mutant c/w WT Primary fibroblasts: ↑ precursor complexes in patients. siRNA knockdown in control cells → IFN induction and proteasome dysfunction Lymphoblastoid cell line: ↑ precursor complexes, ↓ proteasome formation EBV transformed B cells: generally, ↓ chymotryptic like activity Primary keratinocytes: Ubiquitin aggregation	Lmp7^−/− mice	[59,214]
PRP	CARD14	CARD14	AD	GOF	NF-κB		Skin	HEK293T cells: NF-κB luciferase assay Immortalised primary keratinocytes: Expression + NF-κB activity	Nil	[215,216]
Pustular psoriasis	AP1S3	AP1S3	AR	LOF	?NF-κB	IL36 IL-1	Skin	Primary keratinocytes and dermal fibroblasts: abnormal autophagy, accumulation of p62. Abnormal TLR2/6 signalling	Nil	[217,218]
SAVI	TMEM173	STING	AD	GOF	IFN	T1IFN	Multiple incl lungs, vessels	HEK293T cells: IFNB1 reporter assay. Immunoblot analysis of STING pathway CD4, CD8 T cells, CD19 B cells: constitutive STAT1 phosphorylation PBMC and dermal fibroblasts: ↑ IFNB1 transcription at rest. No change with cGAMP exposure. Transcription of TNF and IL-6 ↑ at baseline and with cGAMP treatment	Sting^N153S/+ mice	[16–18]
SPENCD	ACP5	ACP5	AR	LOF	IFN	T1IFN	Multiple	Primary human macrophages: colocalisation studiesPlasmacytoid dendritic cells: co-localisation studies. TLR9 stimulation in shRNA ACP5 knockdown studies → ↑ transcription ISGs HEK293T cells: cotransfection TRAP and osteopontin followed by immunoprecipitation THP1 cells: shRNA ACP5 knockdown studies → ↑ phosphorylation of osteopontin	Acp5^−/− mice	[219–222]
TRAPS	TNFRS1A	TNFR1	AD	Unknown	NF-κB	?IL-1β	Multiple	PBMC: ↑surface expression TNFR1 + ↓shedding (conflicting data) Monocytes: ↑surface expression TNFR1 and ↓shedding; Abnormal autophagy →↑IL-1β + NF-κB activation Dermal fibroblasts: Mutant TNFR1 ↓ receptor shedding Neutrophils: Mutant TNFR1 abnormal retention in cytoplasm HEK293T cells: minor differences in receptor shedding when TNFR1 WT or mutant overexpressed; Cytoplasmic retention and reduced surface expression of mutant	Tnfrsf1a^T50M/+ mice (13) Tnfrsf1a^C33Y/+ mice (232) Tnfrsf1a^p55deltNS mice (10)	[1,9–11,13,223–232]
USP18 deficiency	USP18	USP18	AR	LOF	IFN	T1IFN	CNS Liver	Primary dermal fibroblasts: ↑ transcription ISG after IFN stimulation. Persistent STAT2 phosphorylation. No sig difference in IL-6 response to IL-1β or poly(I:C) .↑ISGylation	Usp18^−/− mice^*	[233]
XLPDR	POLA1	POLA1	XLR	LOF	IFN > NF-κB	T1IFN	Multiple	Primary dermal fibroblasts: ↑IFN + NF-κB response to stimulation with poly(da:dt) or TNF; ↑IRF and NF-κB pathway activation; ↓RNA:DNA levels; Lentiviral transduction of WT rescued phenotype Fibroblast and HeLa cell line: siRNA POLA1 knockdown → ↑ IFN + NF-κB response to stimulation with poly(da:dt) or TNF	Nil	[234]

Abbreviations: AD, autosomal dominant; AIADK, autoinflammation with arthritis and dyskeratosis; AID, autoinflammatory disorder; AIFEC, autoinflammation with infantile enterocolitis; AILJK, autoimmune interstitial lung, joint and kidney disease; AR, autosomal recessive; BLCL, EBV-transformed B-lymphoblastoid cell lines; c/w, compared with; CD, cluster of differentiation; COPA, coatomer subunit α; DIRA, deficiency of IL-1 receptor antagonist; ER, endoplasmic reticulum; FCAS2, familial cold autoinflammatory syndrome 2; GIT, gastrointestinal tract; GOF, gain of function; HIDS, hyper IgD syndrome, HYDM1, hydatidiform molar pregnancy; Inflam, inflammasome; ISG, IFN-stimulated gene; LOF, loss of function; MOI, mode of inheritance; MSPC, multiple self-healing palmoplantar carcinoma; NFATc1, nuclear factor of activated T cell, cytoplasmic 1; ORAS, otulin-related autoinflammatory syndrome; PAAND, pyrin-associated autoinflammation with neutrophilic dermatosis; POLA, DNA polymerase α catalytic subunit; PRP, pityriasis rubra pilaris; SMS, Singleton–Merten syndrome; SPENCD, spondyloenchondrodysplasia; T1IFN, type 1 IFN; XLPDR, x-linked pigmentary disorder, reticulate, with systemic manifestations.

Murine model prior to the description of monogenic condition.