Chronic hepatic involvement in the clinical spectrum of A20 haploinsufficiency

Deshayes, Samuel; Bazille, Céline; Khouri, Elma El; Koné‐Paut, Isabelle; Giurgea, Irina; Georgin-Lavialle, S.; Silva, Nicolas Martin; Dumont, Anaël; Ollivier, Isabelle; Amselem, Serge; Boysson, Hubert de; Aouba, Achille

doi:10.1111/liv.14935

Cited by 13 publications

(17 citation statements)

References 27 publications

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“…The parallels between skin fibrosis in A20 +/− mice and in patients with SSc are underscored by a remarkable degree of gene regulation congruency between mouse and SSc, with 50% of genes sharing deregulated expression in both. Of potential relevance, it was recently reported that some patients with heterozygous loss of function mutations in the TNFAIP3 develop fibrosis in the liver 49 .…”

Section: Discussionmentioning

confidence: 99%

Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs

Wang¹,

Bale

Wei³

et al. 2022

Nat Commun

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In addition to autoimmune and inflammatory diseases, variants of the TNFAIP3 gene encoding the ubiquitin-editing enzyme A20 are also associated with fibrosis in systemic sclerosis (SSc). However, it remains unclear how genetic factors contribute to SSc pathogenesis, and which cell types drive the disease due to SSc-specific genetic alterations. We therefore characterize the expression, function, and role of A20, and its negative transcriptional regulator DREAM, in patients with SSc and disease models. Levels of A20 are significantly reduced in SSc skin and lungs, while DREAM is elevated. In isolated fibroblasts, A20 mitigates ex vivo profibrotic responses. Mice haploinsufficient for A20, or harboring fibroblasts-specific A20 deletion, recapitulate major pathological features of SSc, whereas DREAM-null mice with elevated A20 expression are protected. In DREAM-null fibroblasts, TGF-β induces the expression of A20, compared to wild-type fibroblasts. An anti-fibrotic small molecule targeting cellular adiponectin receptors stimulates A20 expression in vitro in wild-type but not A20-deficient fibroblasts and in bleomycin-treated mice. Thus, A20 has a novel cell-intrinsic function in restraining fibroblast activation, and together with DREAM, constitutes a critical regulatory network governing the fibrotic process in SSc. A20 and DREAM represent novel druggable targets for fibrosis therapy.

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Section: Discussionmentioning

confidence: 99%

Fibroblast A20 governs fibrosis susceptibility and its repression by DREAM promotes fibrosis in multiple organs

Wang¹,

Bale

Wei³

et al. 2022

Nat Commun

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“…In this case, liver function revealed abnormally elevated transaminases, excluding other liver diseases. Recent research reported that patients with HA20 develop chronic liver involvement due to hepatic fibrosis, hepatocyte injury, and/or inflammatory T lymphocyte infiltrates with moderate NF-κB and/or NLRP3 staining ( 15 ). This indicates that HA20 may be present in patients who have multiple concurrent autoimmune diseases, Behcet’s-like symptoms, and unexplained liver function abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Case Report: A novel mutation in TNFAIP3 in a patient with type 1 diabetes mellitus and haploinsufficiency of A20

Cao,

Fu,

Wang

2023

Front. Endocrinol.

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BackgroundHaploinsufficiency of A20 (HA20) is a monogenic autosomal-dominant genetic autoinflammatory disease caused by loss of function mutations in the TNFAIP3 gene. The predominant autoimmune phenotype associated with HA20 varies significantly, presenting with fever, recurrent oral and genital ulcers, skin rash, gastrointestinal and musculoskeletal symptoms, and other clinical manifestations, all of which indicate an early-onset of autoinflammatory disorder. Genetic linkage between TNFAIP3 and T1DM was reported in GWAS studies. However, only a few cases of HA20 combined with T1DM have been reported.Case descriptionA 39-year-old man with a history of type 1 diabetes mellitus since 19 years was admitted to the Department of Endocrinology and Metabolism, First Affiliated Hospital of China Medical University. He also suffered from recurring and minor mouth ulcers since early childhood. His laboratory evaluation results revealed reduced islet function, normal lipid profile, HbA1c of 7%, elevated glutamate decarboxylase antibodies, elevated hepatic transaminases, and elevated thyroid-related antibodies with normal thyroid function. Notably, the patient was diagnosed in adolescence and never had ketoacidosis, the islets were functioning despite the long disease duration, his abnormal liver function could not be reasonably explained, and he had early onset Behcet’s-like disease symptom. Hence, although he was on routine follow-up for diabetes, we communicated with him and obtained consent for genetic testing. Whole-exome sequencing revealed a novel c.1467_1468delinsAT heterozygous mutation in the gene TNFAIP3, which is located in exon 7, resulting in a stop-gained type mutation p.Q490*. With good but mild fluctuating glycemic control, the patient received intensive insulin therapy with long-acting and short-acting insulin. The liver function was improved by using ursodeoxycholic acid 0.75 mg/d during the follow-up.ConclusionWe report a novel pathogenic mutation in TNFAIP3 that results in HA20 in a patient with T1DM. In addition, we analyzed the clinical feathers of such patients and summarized the cases of five patients with HA20 co-presented with T1DM. When T1DM co-occurs with autoimmune diseases or other clinical manifestations, such as oral and/or genital ulcers and chronic liver damage, the possibility of an HA20 must be considered. Early and definitive diagnosis of HA20 in such patients may inhibit the progression of late-onset autoimmune diseases, including T1DM.

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“…Finally, genetic analyses appear also useful to diagnose inflammatory systemic conditions and those associated with a high risk of liver failure. Deshayes et al described the frequent liver involvement in patients with A20 haploinsufficiency, a dominant auto‐inflammatory systemic disorder caused by tumour necrosis factor‐alpha‐induced protein 3 ( TNFAIP3 ) mutations 18 …”

Section: Figurementioning

confidence: 99%