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Case Reports
. 2018 May;77(5):783-786.
doi: 10.1136/annrheumdis-2016-210944. Epub 2017 Jun 28.

Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in TNFAIP3 (A20)

Affiliations
Case Reports

Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in TNFAIP3 (A20)

Christopher J A Duncan et al. Ann Rheum Dis. 2018 May.
No abstract available

Keywords: A20 haploinsufficiency; Complex autoimmunity; Immune homeostasis; Monogenic autoimmunity; NF-κB regulation; Primary immunodeficiency; TNF signalling.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
TNFAIP3 variant identification and functional validation. (A) The family pedigree is shown (triangles are used to preserve the anonymity of healthy unaffected siblings). The first-born infant died as a result of prematurity. Whole exome sequencing data were filtered (Ingenuity Variant Analysis) by confidence (call quality ≥20; read depth ≥10; allele fraction ≥45%); frequency (ExAc allele frequency ≤0.01%); deleteriousness (nonsense/deleterious missense (SIFT/PolyPhen), splice-site disruption); genetic segregation (ie, present in patient and absent from 47 unrelated disease controls) and biological function (linked to phenotype), identifying a single heterozygous frameshift variant in TNFAIP3 (c.1466_1467TGdel). (B) Variant confirmation by Sanger sequencing. (C) The c.1466_1467TGdel variant resulted in a frameshift and premature stop codon (V489Afs*7) in the second ZnF domain and is distinct from previously described mutations in the OTU and ZnF4 domains (blue). (D) V489Afs*7 reduced basal and TNF-induced A20 protein in patient (P) versus control (C1, C2) fibroblasts (immunoblot representative of n=4 independent experiments with n=4 controls). (E) Signalling responses downstream of TNF-α stimulation in patient fibroblasts were exaggerated and prolonged compared with control (immunoblot representative of n=4 independent experiments with n=4 controls). (F) RNA-seq analysis of transcriptional response to 6-hour TNF-α stimulation in patient and control fibroblasts (stimulations performed in triplicate in a single experiment). Top panel: displayed in red are significant (FDR-corrected p≤0.01) DE transcripts regulated ≥4 fold (≥2log2-fold); middle panel: Venn diagram displaying all overlapping DE transcripts ≥2 fold (≥log2-fold); Bottom panel: top 20 significant DE transcripts in patient (red bars) versus control (black bars), demonstrating many major NF-κB target genes. (G) Levels of IL-6 quantified by ELISA in supernatants from patient and control fibroblasts stimulated with TNF-α for 24 hours (mean±SD of average values from two independent experiments in patient and n=4 controls compared by one-sample t-test; **p=0.0015). DE, differentially expressed; FDR, false discovery rate; IL-6, interleukin 6; NF-κB, nuclear factor-κB; OTU, ovarian tumour; PolyPhen, polymorphism phenotyping; SIFT, Sorting Intolerant from Tolerant; TNF-α, tumour necrosis factor-alpha; TNFAIP3, tumour necrosis factor-alpha-induced protein 3; ZnF, zinc finger.

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