A novel missense mutation in TNFAIP3 causes haploinsufficiency of A20

Jiang, Wei; Deng, Mengyue; Gan, Chun Loo; Wang, Li; Mao, Huawei; Li, Qiu

doi:10.1016/j.cellimm.2021.104453

Cited by 9 publications

(7 citation statements)

References 29 publications

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“… GnomAD: Genome Aggregation Database, CADD: Combined Annotation-Dependent Depletion, na: not applicable. * according to the papers reporting the variation: c.305A>G, p.(Asn102Ser) ( Chen et al, 2020a ); c.386C>T, p.(Thr129Met) and c.824T>C, p.(Leu275Pro) ( Aslani et al, 2022 ), c.574G>A, p.(Glu192Lys), c.929T>C, p.(Ile310Thr) and c.2126A>G, p.(Gln709Arg) ( Kadowaki et al, 2021 ), c.728G>A, p.(Cys243Tyr) ( Shigemura et al, 2016 ), c.1428G>A, p.(Met476Ile) ( Dong et al, 2019 ), c.1129G>A, p.(Val377Met) ( Niwano et al, 2022 ), c.1639G>A, p.(Ala547Thr) ( Tian et al, 2022 ), c.1804A>T, p.(Thr602Ser) ( Jiang et al, 2022 ) and c.1939A>C, p.(Thr647Pro)( Mulhern et al, 2019 ). …”

Section: Resultsmentioning

confidence: 99%

“…The hallmark features of HA20 are recurrent fever, painful oral, genital and/or gastrointestinal ulcers with diarrhea, arthralgia, or polyarthritis ( Aeschlimann and Laxer, 2019 ). Since the first description of HA20 ( Zhou et al, 2016 ), more than 25 TNFAIP3 truncating variations have been reported (reviewed in Yu et al, 2020 ) whereas the pathogenic significance has been confirmed for only a part of the 12 reported missense variations ( Aslani et al, 2022 ; Chen et al, 2020a ; Dong et al, 2019 ; Jiang et al, 2022 ; Kadowaki et al, 2021 ; Mulhern et al, 2019 ; Niwano et al, 2022 ; Shigemura et al, 2016 ; Tian et al, 2022 ). Indeed, a body of genetic and experimental evidence is necessary to determine non-ambiguously the deleterious character of missense variations.…”

Section: Introductionmentioning

confidence: 99%

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A critical region of A20 unveiled by missense TNFAIP3 variations that lead to autoinflammation

Khouri

Diab

Louvrier

et al. 2023

eLife

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A20 haploinsufficiency (HA20) is an autoinflammatory disease caused by heterozygous loss-of-function variations in TNFAIP3, the gene encoding the A20 protein. Diagnosis of HA20 is challenging due to its heterogeneous clinical presentation and the lack of pathognomonic symptoms. While the pathogenic effect of TNFAIP3 truncating variations is clearly established, that of missense variations is difficult to determine. Herein, we identified a novel TNFAIP3 variation, p.(Leu236Pro), located in the A20 ovarian tumor (OTU) domain and demonstrated its pathogenicity. In the patients’ primary cells, we observed reduced A20 levels. Protein destabilization was predicted in silico for A20_Leu236Pro and enhanced proteasomal degradation was confirmed in vitro through a flow cytometry-based functional assay. By applying this approach to the study of another missense variant, A20_Leu275Pro, for which no functional characterization has been performed to date, we showed that this variant also undergoes enhanced proteasomal degradation. Moreover, we showed a disrupted ability of A20_Leu236Pro to inhibit the NF-κB pathway and to deubiquitinate its substrate TRAF6. Structural modeling revealed that two residues involved in OTU pathogenic missense variations (i.e. Glu192Lys and Cys243Tyr) establish common interactions with Leu236. Interpretation of newly identified missense variations is challenging, requiring, as illustrated here, functional demonstration of their pathogenicity. Together with functional studies, in silico structure analysis is a valuable approach that allowed us (i) to provide a mechanistic explanation for the haploinsufficiency resulting from missense variations and (ii) to unveil a region within the OTU domain critical for A20 function.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A critical region of A20 unveiled by missense TNFAIP3 variations that lead to autoinflammation

Khouri

Diab

Louvrier

et al. 2023

eLife

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“…One widely used cell line in SAIDs research is THP‐1, 40 , 41 , 42 , 43 , 44 , 45 , 46 a monocyte‐like cell line isolated from an acute myeloid leukaemia patient. 47 This line is morphologically and functionally similar to monocytes and can be differentiated in vitro into macrophage‐like cells.…”

Section: Cell Linesmentioning

confidence: 99%

Cellular models in autoinflammatory disease research

Şen,

Balcı‐Peynircioğlu

2024

Clin & Trans Imm

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Systemic autoinflammatory diseases are a heterogeneous group of rare genetic disorders caused by dysregulation of the innate immune system. Understanding the complex mechanisms underlying these conditions is critical for developing effective treatments. Cellular models are essential for identifying new conditions and studying their pathogenesis. Traditionally, these studies have used primary cells and cell lines of disease‐relevant cell types, although newer induced pluripotent stem cell (iPSC)‐based models might have unique advantages. In this review, we discuss the three cellular models used in autoinflammatory disease research, their strengths and weaknesses, and their applications to inform future research in the field.

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“…Hypomorphic mutations in the OTULIN gene, resulting in elevated NFKB activity, cause ORAS, also named “otulipenia”, which is characterized by inflammatory skin signs with panniculitis starting during the neonatal period and responding to TNF inhibitors [ 65 ]. Similarly, heterozygous haploinsufficient mutations in the A20 (TNFAIP3) gene cause abnormal ubiquitination patterns, giving rise to aberrant ubiquitination and NFKB upregulation [ 66 ]. Table 5 lists the general manifestations at onset of NFKB-diseases in childhood.…”

Section: An Overview Of the Nfkb-related Autoinflammatory Disordersmentioning

confidence: 99%

The Clinical Chameleon of Autoinflammatory Diseases in Children

Sangiorgi

Rigante

2022

Cells

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The very first line of defense in humans is innate immunity, serving as a critical strongpoint in the regulation of inflammation. Abnormalities of the innate immunity machinery make up a motley group of rare diseases, named ‘autoinflammatory’, which are caused by mutations in genes involved in different immune pathways. Self-limited inflammatory bouts involving skin, serosal membranes, joints, gut and other districts of the human body burst and recur with variable periodicity in most autoinflammatory diseases (ADs), often leading to secondary amyloidosis as a long-term complication. Dysregulated inflammasome activity, overproduction of interleukin (IL)-1 or other IL-1-related cytokines and delayed shutdown of inflammation are pivotal keys in the majority of ADs. The recent progress of cellular biology has clarified many molecular mechanisms behind monogenic ADs, such as familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome (or ‘autosomal dominant familial periodic fever’), cryopyrin-associated periodic syndrome, mevalonate kinase deficiency, hereditary pyogenic diseases, idiopathic granulomatous diseases and defects of the ubiquitin-proteasome pathway. A long-lasting history of recurrent fevers should require the ruling out of chronic infections and malignancies before considering ADs in children. Little is known about the potential origin of polygenic ADs, in which sterile cytokine-mediated inflammation results from the activation of the innate immunity network, without familial recurrency, such as periodic fever/aphthous stomatitis/pharyngitis/cervical adenopathy (PFAPA) syndrome. The puzzle of febrile attacks recurring over time with chameleonic multi-inflammatory symptoms in children demands the inspection of the mixture of clinical data, inflammation parameters in the different disease phases, assessment of therapeutic efficacy of a handful of drugs such as corticosteroids, colchicine or IL-1 antagonists, and genotype analysis to exclude or confirm a monogenic origin.

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A novel missense mutation in TNFAIP3 causes haploinsufficiency of A20

Cited by 9 publications

References 29 publications

A critical region of A20 unveiled by missense TNFAIP3 variations that lead to autoinflammation

A critical region of A20 unveiled by missense TNFAIP3 variations that lead to autoinflammation

Cellular models in autoinflammatory disease research

The Clinical Chameleon of Autoinflammatory Diseases in Children

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