Novel Heterogeneous Mutation of TNFAIP3 in a Chinese Patient with Behçet-Like Phenotype and Persistent EBV Viremia

Dong, Xinxin; Liu, Luyao; Wang, Ying; Yang, Xingliang; Wang, Wenjie; Lin, Liang-In; Sun, Bijun; Hou, Jia‐Woei; Ying, Wenjing; Hui, Xiaoying; Zhou, Qinhua; Liu, Danru; Yao, Haili; Sun, Jinqiao; Wang, Xiaochuan

doi:10.1007/s10875-019-00604-9

Cited by 24 publications

(23 citation statements)

References 34 publications

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“…All identified pathogenic variants were heterozygous frameshift or nonsense variants in TNFAIP3 causing haploinsufficiency of the A20 protein (HA20). The effect of heterozygous missense variants on protein function is yet unclear, although they have been reported in some families 150,151 . Experiments using patient lymphocytes and fibroblasts showed increased Lys63‐ubiquitination of NEMO, increased phosphorylation of IKKα/IKKβ, and increased degradation of IκBα upon TNF stimulation.…”

Section: Primarily Inflammationmentioning

confidence: 99%

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Schnappauf

Aksentijevich

2020

Journal of Leukocyte Biology

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NF-B is a master transcription factor that activates the expression of target genes in response to various stimulatory signals. Activated NF-B mediates a plethora of diverse functions including innate and adaptive immune responses, inflammation, cell proliferation, and NF-B is regulated through interactions with I B inhibitory proteins, which are in turn regulated by the inhibitor of B kinase (IKK) complex. Together, these 3 components form the core of the NF-B signalosomes that have cell-specific functions which are dependent on the interactions with other signaling molecules and pathways. The activity of NF-B pathway is also regulated by a variety of post-translational modifications including phosphorylation and ubiquitination by Lys63, Met1, and Lys48 ubiquitin chains. The physiologic role of NF-B is best studied in the immune system due to discovery of many human diseases caused by pathogenic variants in various proteins that constitute the NF-B pathway. These disease-causing variants can act either as gain-of-function (GoF) or loss-of-function (LoF) and depending on the function of mutated protein, can cause either immunodeficiency or systemic inflammation. Typically, pathogenic missense variants act as GoF and they lead to increased activity in the pathway. LoF variants can be inherited as recessive or dominant alleles and can cause either a decrease or an increase in pathway activity. Dominantly inherited LoF variants often result in haploinsufficiency of inhibitory proteins. Here, we review human Mendelian immunologic diseases, which results from mutations in different molecules in the canonical NF-B pathway and surprisingly present with a continuum of clinical features including immunodeficiency, atopy, autoimmunity, and autoinflammation.

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Section: Primarily Inflammationmentioning

confidence: 99%

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Schnappauf

Aksentijevich

2020

Journal of Leukocyte Biology

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“…Indeed, whole exome sequencing in familial BD has now found several families with dominant loss-of-function mutations in TNFAIP3. 59,[61][62][63][64][65] Simultaneously, the same group also identified two missense and one frameshift OTULIN autosomal recessive mutations in three distinct families with four affected patients with an BD-resembling autoinflammatory phenotype. 66 Patients presented with neonatal onset fever, neutrophilic dermatitis or severe panniculitis and failure to thrive, but without obvious primary immunodeficiency, culminating with a clinical condition named Otulipenia.…”

Section: Tumour Necrosis Factor α-Induced Protein 3 (Tnfaip3) and mentioning

confidence: 99%

“…Furthermore, mutant A20 is likely to act through haploinsufficiency and patient‐derived cells showed increased degradation of IκBα and nuclear translocation of the NF‐κB p65 subunit together with increased expression of NF‐κB‐mediated pro‐inflammatory cytokines. Indeed, whole exome sequencing in familial BD has now found several families with dominant loss‐of‐function mutations in TNFAIP3 59,61‐65 …”

Section: New Insights: Nf‐κb Pathway Mutationsmentioning

confidence: 99%

Behçet disease (BD) and BD‐like clinical phenotypes: NF‐κB pathway in mucosal ulcerating diseases

et al. 2020

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Behçet's disease (BD) is a heterogeneous multi-organ disorder in search of a unified pathophysiological theory and classification. The disease frequently has overlapping features resembling other disease clusters, such as vasculitides, spondyloarthritides and thrombophilias with similar genetic risk variants, namely HLA-B*51, ERAP1, IL-10, IL-23R. Many of the BD manifestations, such as unprovoked recurrent episodes of inflammation and increased expression of IL-1, IL-6 and TNFα, overlap with those of the hereditary monogenic autoinflammatory syndromes, positioning BD at the crossroads between autoimmune and autoinflammatory syndromes. BDlike disease associates with various inborn errors of immunity, including familial Mediterranean fever, conditions related to dysregulated NF-κB activation (eg TNFAIP3, NFKB1, OTULIN, RELA, IKBKG) and either constitutional trisomy 8 or acquired trisomy 8 in myelodysplastic syndromes. We review here the recent advances in the immunopathology of BD, BD-like diseases and the NF-κB pathway suggesting new elements in the elusive BD etiopathogenesis.

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“…As previously reported [13], serum IgG, IgA and IgM were determined by an automated clinical chemistry analyzer (Erba Diagnostics, Mannheim, Germany). IgG (Cat.…”

Section: Serum Immunoglobulin and Lymphocyte Subset Detectionmentioning

confidence: 99%

The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations

Wang

Sun

Liu

et al. 2020

Allergy Asthma Clin Immunol

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Background Loss-of-function (LOF) mutations in signal transducer and activator of transcription 3 (STAT3) is one of the causes of STAT3 hyperimmunoglobulin E (IgE) syndrome (STAT3-HIES), while gain-of-function (GOF) mutations in STAT3 lead to immune dysregulation diseases. We retrospectively analyzed the age, common clinical symptoms, immunologic and molecular manifestations in 11 patients with LOF STAT3 mutations and 1 patient with a GOF STAT3 mutation. Methods Twelve patients were enrolled in our study. Serum immunoglobulin measurements, lymphocyte subset detection and whole-exome sequencing were performed. Results The median age at diagnosis of STAT3-HIES patients was 4.74 years. Eczema, recurrent respiratory infections, fevers, abscesses and Staphylococcus aureus infections were the classic manifestations. Elevated serum IgE levels are not always observed in conjunction with high eosinophil counts. A moderate viral DNA load was also measured in peripheral blood mononuclear cells. We noticed that c. 1144C>T was the most common mutation site, followed by c.1311C>A. Additionally, c.1311C>A and c. 1826G>C are two novel mutations. Eight patients achieved notable improvement after receiving intravenous immunoglobulin. Conclusion We updated the current knowledge of this topic. We found an earlier median age at diagnosis, a higher survival rate, and a general lack of nonimmunological abnormalities; we also described the treatment details and novel mutations involve in STAT3-HIES and compared STAT3 LOF and GOF mutations.

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Novel Heterogeneous Mutation of TNFAIP3 in a Chinese Patient with Behçet-Like Phenotype and Persistent EBV Viremia

Cited by 24 publications

References 34 publications

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Behçet disease (BD) and BD‐like clinical phenotypes: NF‐κB pathway in mucosal ulcerating diseases

The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations

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