Large deletion in 6q associated to A20 haploinsufficiency and thoracoabdominal heterotaxy

Viel, Sébastien; Cheyssac, Elodie; Pescarmona, Rémi; Besson, Laurie; Till, Marianne; Viremouneix, L.; Touitou, Isabelle; Sarrabay, Guillaume; Walzer, Thierry; Belot, Alexandre

doi:10.1136/annrheumdis-2018-213300

Cited by 13 publications

(3 citation statements)

References 10 publications

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“…However, this did not reach a statistical significance (Figure 2 ). Similarly, spontaneous phosphorylation of p65 NF-κB has been recently reported for a patient with TNFAIP3 deletion ( 8 ).…”

Section: Clinical and Laboratory Investigationssupporting

confidence: 63%

A Case of Adult-Onset Still’s Disease Caused by a Novel Splicing Mutation in TNFAIP3 Successfully Treated With Tocilizumab

et al. 2018

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TNFAIP3 encodes the NF-κB regulatory protein A20. High-penetrance heterozygous mutations in TNFAIP3 cause a haploinsufficiency of A20 (HA20), inadequate inhibition of NF-κB pathway, and an early onset autoinflammatory disorder. However, the clinical phenotype of patients with HA20 varies greatly and clinical diagnoses prior to establishing the genetic cause, included both autoimmune and autoinflammatory conditions. Here, we present the first patient with HA20, who was previously diagnosed with AOSD but was later found to have a novel heterozygous variant in TNFAIP3 and who was successfully treated with anti-IL6 receptor biologic tocilizumab (RoActemra). We discovered a novel heterozygous mutation in TNFAIP3 c.1906C>T, not previously found in ExAC database. Further analysis shows that this single-nucleotide variant at the terminal residue of TNFAIP3 exon 7 produces an alternatively spliced mRNA resulting in p.His636fsTer1. Additional genetic analysis of family members shows that this variant does segregate with the inflammatory clinical phenotypes. Subsequent functional test show that NF-κB activation, measured as intracellular phosphorylation of p65 in CD14 + monocytes, was more enhanced in the patient compared with healthy controls (HC) following stimulation with LPS. This was associated with higher production of inflammatory cytokines by the patients PBMC in response to LPS and ATP and enhanced activation of NLRP3 inflammasome complex. Furthermore, increased activation of NLRP3 inflammasome was evident systemically, since we detected higher levels of ASC specks in patients’ sera compared with HC. Finally, we used population genetics data from GnomAD to construct a map of both genetic conservation and most probable disease-causing variants in TNFAIP3 which might be found in future cases of HA20.

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Section: Clinical and Laboratory Investigationssupporting

confidence: 63%

A Case of Adult-Onset Still’s Disease Caused by a Novel Splicing Mutation in TNFAIP3 Successfully Treated With Tocilizumab

et al. 2018

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“…There is substantial variability in expressivity of disease even among patients with the same genotype. Recently, large deletions on chromosome 6 encompassing up to 55 genes including TNFAIP3 , were identified in patients with systemic inflammation, psychomotor and growth delay, and situs inversus (87, 88). The heterotaxy (abnormal organ arrangement) was likely the consequence of the deleted CITED2 gene (89, 90).…”

Section: Post-translation Modifying Enzymes In Autoinflammatory Diseasesmentioning

confidence: 99%

Biochemistry of Autoinflammatory Diseases: Catalyzing Monogenic Disease

Beck

Aksentijevich

2019

Front. Immunol.

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Monogenic autoinflammatory disorders are a group of conditions defined by systemic or localized inflammation without identifiable causes, such as infection. In contrast to classical primary immunodeficiencies that manifest with impaired immune responses, these disorders are due to defects in genes that regulate innate immunity leading to constitutive activation of pro-inflammatory signaling. Through studying patients with rare autoinflammatory conditions, novel mechanisms of inflammation have been identified that bare on our understanding not only of basic signaling in inflammatory cells, but also of the pathogenesis of more common inflammatory diseases and have guided treatment modalities. Autoinflammation has further been implicated as an important component of cardiovascular, neurodegenerative, and metabolic syndromes. In this review, we will focus on a subset of inherited enzymatic deficiencies that lead to constitutive inflammation, and how these rare diseases have provided insights into diverse areas of cell biology not restricted to immune cells. In this way, Mendelian disorders of the innate immune system, and in particular loss of catalytic activity of enzymes in distinct pathways, have expanded our understanding of the interplay between many seemingly disparate cellular processes. We also explore the overlap between autoinflammation, autoimmunity, and immunodeficiency, which has been increasingly recognized in patients with dysregulated immune responses.

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“…En plus de ces deux séries importantes, 10 autres patients sont décrits avec des tableaux d'aphtose et de fièvre récurrente ce qui porte à 51 le nombre de patients publiés au total à ce jour et résumés dans les tables 2 et 3. Par souci de clarté, une observation bien différente associant un syndrome polymalformatif, une vascularite récurrente à IgA et une autoimmunité mais sans fièvre récurrente due à une large délétion comprenant 60 gènes sur le chromosome 6 p dont CITED2, IFNGR1 et TNFAIP3 n'a pas été incluse dans la table 3[21] .…”

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Autoinflammation secondaire à des défauts d’ubiquitination dans la voie NFKB : haploinsuffisance de A20 (HA20) et déficit en Otuline (Otulinopénie)

Koné‐Paut

Georgin‐Lavialle

Galeotti

et al. 2019

Revue du Rhumatisme

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Large deletion in 6q associated to A20 haploinsufficiency and thoracoabdominal heterotaxy

Cited by 13 publications

References 10 publications

A Case of Adult-Onset Still’s Disease Caused by a Novel Splicing Mutation in TNFAIP3 Successfully Treated With Tocilizumab

A Case of Adult-Onset Still’s Disease Caused by a Novel Splicing Mutation in TNFAIP3 Successfully Treated With Tocilizumab

Biochemistry of Autoinflammatory Diseases: Catalyzing Monogenic Disease

Autoinflammation secondaire à des défauts d’ubiquitination dans la voie NFKB : haploinsuffisance de A20 (HA20) et déficit en Otuline (Otulinopénie)

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