Table 1.

Comparison of genetics and mechanisms of disease in otulipenia, haploinsufficiency of A20 (HA20), and linear ubiquitin chain assembly complex (LUBAC) deficiencies.

		Otulipenia/ORAS	HA20
Gene	Gene name	OTULIN (FAM105B)	TNFAIP3
	Exons	7 exons	9 exons
	Chromosome	Chr.5	Chr.6
Protein	Protein name	OTULIN	A20
	Protein length	352aa	790aa
	Protein domains	PUB-interacting motif domain, ovarian tumor (OTU) domain	OTU domain, 7 ZnF domains
	Protein function	Met1 linear deubiquitinase (DUB)	K63 DUB
	Involved pathway	NF-κB	NF-κB, NLRP3
	Substrate molecules	NEMO, TNF receptor 1 (TNFR1), RIPK1, ASC	NEMO, RIPK1, TRAF6, pro IL-1β
Genetics	Inheritance	Recessive	Dominant
	Type of mutations	Loss-of-function mutations (missense, INDELS)	Loss-of-function mutations (stop gain mutation, missense, INDELS)
	Frequency of mutant alleles	Rare or novel	Novel
	Location of the mutations	OTU domain (linear DUB activity)	OTU domain (k63 DUB activity) or ZnF4 domain
	Number of mutations	Biallelic (compound heterozygous or homozygous)	Heterozygous
Mechanisms	Mechanism	Loss-of-function (reduced protein expression)	Haploinsufficiency (50% decrease in protein expression)
	Protein Interactions	Instability of LUBAC	Decreased association with TNFR1, TRAF2, and RIPK1
	Effect of mutant proteins	Impaired linear deubiquitination of NEMO, TNFR1, RIPK1, ASC	Impaired K63 deubiquitination of NEMO, RIPK1, and TRAF6
	Involved pathway	Increased signaling in NF-κB and mitogen-activated protein kinases (MAPK) pathways	Increased activity of NF-κB, MAPKs, and NLRP3
	Cytokines	IL-1β, TNF, IL-6, IL-12, IL-18, IFNγ	IL-1β, TNF, IL-6, IL-9, IL-17, IL-18, IFNγ
		HOIL-1 deficiency	HOIP deficiency
Gene	Gene name	RBCK1	RNF31
	Exons	12 exons	21 exons
	Chromosome	Chr.20	Chr.14
Protein	Protein name	HOIL-1	HOIP
	Protein length	510aa	1,072aa
	Protein domains	Ubiquitin-like (UBL), novel zinc finger (NZF), RING1, IBR, RING2	PUB, ZnF, NZF1, NZF2, UBA, RING1, IBR, RING2, LDD
	Protein function	Subunit of the LUBAC	Catalytic subunit of the LUBAC
	Involved pathway	NF-κB signaling pathway	NF-κB signaling pathway
Mutations	Type of mutations	Loss-of-function mutations (stop gain mutation, INDELS)	Loss-of-function mutations (missense)
	Frequency of mutant alleles	Rare or novel	Novel
	Location of the mutations	UBL domain (interacts with HOIP UBA domain), NZF domain (ubiquitin binding)	PUB domain (interacts with OTULIN)
	Number of mutations	Biallelic (compound heterozygous or homozygous)	Biallelic (homozygous)
Mechanisms	Inheritance	Recessive	Recessive
	Mechanism	Loss-of-function (decreased protein expression, instability of LUBAC, impaired linear ubiquitination)	Loss-of-function (decreased protein expression, instability of LUBAC, impaired linear ubiquitination)
	Effect of mutant proteins	Defect in linear ubiquitination NEMO, RIPK1, IRAK-1	Defect in linear ubiquitination
	Involved pathway	Impaired NF-κB activation in fibroblasts, increased NF-κB activity in monocytes	Impaired NF-κB activation in fibroblasts and CD40L stimulated B cells, increased NF-κB activity in monocytes
	Cytokines	Impaired expression of IL-6 in fibroblasts upon IL-1β and TNF stimulation; hyperproduction of IL-6 upon in IL-1β stimulated monocytes; high serum IL-1, IL-6	Hyperproduction of IL-6 in IL-1β stimulated monocytes