Novel loss-of-function mutations in TNFAIP3 gene in patients with lupus nephritis

Abstract

Background Heterozygous loss-of-function mutations in the TNFAIP3 gene cause an early-onset autoinflammatory disease named haploinsufficiency of A20 (HA20). Here we described three unrelated patients with autoimmune lupus nephritis (LN) phenotypes carrying three novel mutations in the TNFAIP3 gene. Methods Whole-exome sequencing (WES) was used to identify the causative mutations in three biopsy-proven LN patients. Sanger sequencing and quantitative PCR (qPCR) were used to validate the mutations identified by WES. RNA sequencing, qPCR, Cytometric Bead Array was used to detect inflammatory signature in the patients. Results The patients predominantly presented with autoimmune phenotype, including autoimmune haemolytic anaemia, multipositive autoantibodies, and LN. Additionally, novel phenotypes of allergy, and pericardial effusion were first reported. WES identified three novel heterozygous mutations in the TNFAIP3 gene, including a novel splicing mutation located in the canonical splicing site (c.634 + 2T > C) resulting in an intron4 insertion containing a premature stop codon, a de novo novel copy number variation (exons7-8 deletion), and a novel nonsense mutation c.1300_1301delinsTA causing a premature stop codon. We further identified hyperactivation signatures of NF-κB and type-I IFN signalling and overproduction of pro-inflammatory cytokines in blood. This report expand the phenotype to later age, as two girls were diagnosed at age 3 years and one man at age 29 years. Conclusions Kidney involvement may be the main feature of the clinical spectrum of HA20, even in adults. Genetic screening should be considered for early-onset LN patients.

Kidney Involvement in Autoinflammatory Diseases

“…The patient received anti-TNF etanercept in combination with hydroxychloroquine, prednisolone, and MMF, which displayed good efficacy. We recently also reported 3 patients with HA20 presenting with LN, including one adult and two children [91]. Kidney biopsy showed class IV LN in 2 patients and class V LN in one patient.…”

Gain-of-function TLR7 and loss-of-function A20 gene variants identify a novel pathway for Mendelian lupus and lupus nephritis

“…Although there is no specific treatment available for most IKDs, a correct diagnosis may prevent unnecessary invasive procedures and treatments and, as IKD can be directly attributed to the dysfunction of the responsible gene, this may lead to the design and development of specific therapies [ 15 ]. Recent reports have also provided a genetic basis for some forms of LN [ 18 ].…”

“…Loss-of-function (LOF) variants of tumor necrosis factor alpha–induced protein 3 ( TNFAIP3) and gain of function (GOF) variants of Toll-like receptor 7 ( TLR7 ) were recently reported to underlie LN in children and adults in the Clinical Kidney Journal ( CKJ ) and Nature , respectively [ 18 , 25 ].…”

“…The introduction of the TLR7-Y264H variant in mice resulted in SLE characterized by autoimmunity, tissue injury and inflammation, including LN, and this was prevented by Myd88 deficiency [ 25 ]. Also recently, LOF mutations in TNFAIP3 decisively contribute to loss of tolerance and LN [ 18 ]. BCR: B-cell receptor; IFNAR: interferon-α/β receptor; ssRNA: single-stranded RNA.…”

“…In this issue of CKJ , Zhang et al [ 18 ]. report that HA20 is a cause of biopsy-proven LN with both early and late onset in males and females in three families with different TNFAIP3 variants.…”