A NOVEL HOMOZYGOUS E781K A20/TNFAIP3 GENE MUTATION IS RESPONSIBLE FOR THE EARLY ONSET OF MONOGENIC LUPUS

Abstract

Systemic Lupus Erythematosus (SLE) is a complex systemic autoimmune disease, with great variability in its clinical manifestations and prognosis. Genome-wide association studies (GWAS) have identified over 50 loci associated with SLE, however, the identified SLE risk variants are common variants accounting for less than 30% of disease heritability. The study of rare monogenic lupus has provided insights into better understanding pathogenesis of SLE. Here, we describe a novel case of an early-onset recessive monogenic lupus-like disease. Whole exome sequencing identified a homozygous missense mutation (E781K) in the TNFAIP3 gene in the affected proband. The father and one sibling of the proband were heterozygous for the E781K mutation and were healthy. TNFAIP3 codes for the A20 protein, a potent negative regulator of the NF-κB pro-inflammatory pathway. The missense mutation was predicted to be damaging by deleteriousness prediction algorithms, and structural modeling demonstrated that the mutation significantly changes the structure of A20 zinc finger 7 domain which inhibits the NF-κB pathway by binding linear polyubiquitin. Hence, we hypothesized that the homozygous E781K missense mutation leads to partial loss of function of A20 protein, leading to attenuated suppression of the NF-κB pathway and onset of autoinflammatory monogenic lupus in the proband. We performed a NF-κB luciferase reporter assay to compare the inhibitory effects of E781K A20 mutant versus A20 wildtype in TNF- α stimulated HEK293T cells. Our results showed that the E781K A20 mutant failed to suppress the NF-κB pathway as efficiently as A20 wildtype, leading to greater activation of the pathway, but still inhibited the pathway when compared to untransfected cells. Hence, our results supported our hypothesis that the homozygous E781K mutation leads to partial loss of function of A20 protein, causing early-onset, monogenic recessive lupus.

Date of Award	2019
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences