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Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an
early-onset autoinflammatory disease
#MMPMID26642243
Zhou Q
; Wang H
; Schwartz DM
; Stoffels M
; Park YH
; Zhang Y
; Yang D
; Demirkaya E
; Takeuchi M
; Tsai WL
; Lyons JJ
; Yu X
; Ouyang C
; Chen C
; Chin DT
; Zaal K
; Chandrasekharappa SC
; Hanson EP
; Yu Z
; Mullikin JC
; Hasni SA
; Wertz IE
; Ombrello AK
; Stone DL
; Hoffmann P
; Jones A
; Barham BK
; Leavis HL
; van Royen-Kerkof A
; Sibley C
; Batu ED
; Gül A
; Siegel RM
; Boehm M
; Milner JD
; Ozen S
; Gadina M
; Chae J
; Laxer RM
; Kastner DL
; Aksentijevich I
Nat Genet
2016[Jan]; 48
(1
): 67-73
PMID26642243
show ga
Systemic autoinflammatory diseases are driven by abnormal activation of innate
immunity. Herein we describe a new disease caused by high-penetrance heterozygous
germline mutations in TNFAIP3, which encodes the NF-?B regulatory protein A20, in
six unrelated families with early-onset systemic inflammation. The disorder
resembles Behçet's disease, which is typically considered a polygenic disorder
with onset in early adulthood. A20 is a potent inhibitor of the NF-?B signaling
pathway. Mutant, truncated A20 proteins are likely to act through
haploinsufficiency because they do not exert a dominant-negative effect in
overexpression experiments. Patient-derived cells show increased degradation of
I?B? and nuclear translocation of the NF-?B p65 subunit together with increased
expression of NF-?B-mediated proinflammatory cytokines. A20 restricts NF-?B
signals via its deubiquitinase activity. In cells expressing mutant A20 protein,
there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1
after stimulation with tumor necrosis factor (TNF). NF-?B-dependent
proinflammatory cytokines are potential therapeutic targets for the patients with
this disease.
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