Autosomic dominant familial Behçet disease and haploinsufficiency A20: A review of the literature

Berteau, Florian; Rouvière, Bénédicte; Delluc, Aurélien; Nau, Alice; Berre, Rozenn Le; Sarrabay, Guillaume; Touitou, Isabelle; Moreuil, Claire de

doi:10.1016/j.autrev.2018.02.012

Cited by 67 publications

(70 citation statements)

References 24 publications

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“…This newly identified autoinflammatory disease is characterized by recurrent oral (87%) and genital (67%) ulcers, arthralgia or arthritis (42%), and skin involvement (53%), such as erythema nodosum or abdominal symptoms (60%). 12 In the present case, the c.547C>T (p.R183*) variant in exon 4 of the nine total exons of the TNFAIP3 gene (NM_001270508) is in an OTU domain, similar to most previously reported cases of AISBL. 12 The variant was predicted to be disease-causing by Mutation Taster, leading to a truncated protein and a haploinsufficiency A20.…”

Section: Discussionsupporting

confidence: 82%

“…12 In the present case, the c.547C>T (p.R183*) variant in exon 4 of the nine total exons of the TNFAIP3 gene (NM_001270508) is in an OTU domain, similar to most previously reported cases of AISBL. 12 The variant was predicted to be disease-causing by Mutation Taster, leading to a truncated protein and a haploinsufficiency A20.…”

Section: Discussionsupporting

confidence: 82%

“…A20 is a powerful inhibitor of the nuclear factor (NF)‐κB activation signaling pathway by TNF‐α. Decreasing A20 will result in interleukin (IL)‐1β overproduction and an autoinflammatory or autoimmune disease. This newly identified autoinflammatory disease is characterized by recurrent oral (87%) and genital (67%) ulcers, arthralgia or arthritis (42%), and skin involvement (53%), such as erythema nodosum or abdominal symptoms (60%) .…”

Section: Discussionmentioning

confidence: 99%

“…Decreasing A20 will result in interleukin (IL)‐1β overproduction and an autoinflammatory or autoimmune disease. This newly identified autoinflammatory disease is characterized by recurrent oral (87%) and genital (67%) ulcers, arthralgia or arthritis (42%), and skin involvement (53%), such as erythema nodosum or abdominal symptoms (60%) . In the present case, the c.547C>T (p.R183 * ) variant in exon 4 of the nine total exons of the TNFAIP3 gene (NM_001270508) is in an OTU domain, similar to most previously reported cases of AISBL .…”

Section: Discussionmentioning

confidence: 99%

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Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

Liang

Zhang

Guo

et al. 2019

The Journal of Dermatology

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Generalized pustular psoriasis (GPP) is now known to be caused by biallelic variants in IL36RN and monoallelic variants in CARD14 and AP1S3. The presence of a modifier locus or oligogenic inheritance have been hypothesized. We report on a patient with a unique coinheritance of pathogenic variants in IL36RN (c.115+6T>C) and TNFAIP3 (c.547C>T, p.R183*) causing the genetic entities GPP and familial Behçet‐like autoinflammatory syndrome (AISBL). The heterozygous variant in IL36RN identified by Sanger sequencing was inherited from his unaffected father, while the heterozygous variant in TNFAIP3 was detected by whole‐exome sequencing and was also identified in the patient's AISBL‐affected maternal relatives. Further functional studies are required to research whether the variant of TNFAIP3 plays a part in the development of GPP or simply causes the Behçet's disease phenotype. However, our data suggest that whole‐exome sequencing for the heterozygous carrier of the IL36RN gene in GPP be used to find the potential second genetic locus.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

Liang

Zhang

Guo

et al. 2019

The Journal of Dermatology

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“…The TNFAIP3 gene encodes a zinc finger protein and ubiquitin-editing enzyme, and variants in TNFAIP3 have been associated with autoinflammatory syndrome (OMIM #616744) characterized by hemolytic anemia, thrombocytopenia, autoinflammation, and autoimmune lymphoproliferative syndrome, the latter presenting with lymphadenopathy and hepatosplenomegaly (23). The variant harbored by P10 has not been described previously, and we have not been able to verify whether the variant is de novo or inherited; however a p.A332X mutation has been reported in autosomal dominant familial Behçet disease and haploinsufficiency of A20 (35). The variant in P10 is located in the ovarian tumor (OUT) domain as described for p.A332X, resulting in a severely truncated and rapidly degraded protein (35).…”

Section: Identified Variantsmentioning

confidence: 81%

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

et al. 2020

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Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by recurrent bacterial infections and defined by reduced levels of IgG, IgA, and/or IgM, insufficient response to polysaccharide vaccination, and an abnormal B-cell immunophenotype with a significantly reduced fraction of isotype-switched memory B cells. In addition to this infectious phenotype, at least one third of the patients experience autoimmune, autoinflammatory, granulomatous, and/or malignant complications. The very heterogeneous presentation strongly suggests a collection of different disease entities with somewhat different pathogeneses and most likely diverse genetic etiologies. Major progress has been made during recent years with the advent and introduction of next-generation sequencing, initially for research purposes, but more recently in clinical practice. In the present study, we performed whole exome sequencing on 20 CVID patients with autoimmunity, autoinflammation, and/or malignancy from the Danish CVID cohort with the aim to identify gene variants with a certain, possible, or potential disease-causing role in CVID. Through bioinformatics analyses, we identified variants with possible/probable disease-causing potential in nine of the patients. Of these, three patients had four variants in three different genes classified as likely pathogenic (NFKB1, TNFAIP3, and TTC37), whereas in six patients, we identified seven variants of possible pathogenic potential classified as variants of unknown significance (STAT3, IL17F, IRAK4, DDX41, NLRC3, TNFRSF1A, and PLCG2). In the remaining 11 patients, we did not identify possible genetic causes. Genetic findings were correlated to clinical disease presentation, clinical immunological phenotype, and disease complications. We suggest that the variants identified in the present work should lay the ground for future studies to functionally validate their disease-causing potential and to investigate at the mechanistic and molecular level their precise role in CVID pathogenesis. Overall, we believe that the present work contributes important new insights into the genetic basis of CVID and particular in the subset of CVID patients with a complex phenotype involving not only infection, but also autoimmunity, autoinflammation, and malignancy.

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A Novel RELA Truncating Mutation in a Familial Behçet’s Disease–like Mucocutaneous Ulcerative Condition

Adeeb

Dorris

Morgan

et al. 2021

Arthritis & Rheumatology

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Objective. Monogenic Behçet's disease (BD)-like conditions are increasingly recognized and to date have been found to predominantly involve loss-of-function variants in TNFAIP3. This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD-like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls). Methods. Whole-exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v-rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA −/− mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF-κB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild-type and truncated RELA in experimental systems and patient samples. Results. A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA −/− mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild-type RELA; however, there was no difference in RELA nuclear translocation. In RelA −/− MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98-fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild-type RELA (P = 0.036). Conclusion. Our data indicate that RELA loss-of-function mutations cause BD-like autoinflammation and NMO via impaired NF-κB signaling and increased apoptosis.

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Autosomic dominant familial Behçet disease and haploinsufficiency A20: A review of the literature

Cited by 67 publications

References 24 publications

Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

Identification of Novel Genetic Variants in CVID Patients With Autoimmunity, Autoinflammation, or Malignancy

A Novel RELA Truncating Mutation in a Familial Behçet’s Disease–like Mucocutaneous Ulcerative Condition

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