Autosomal recessive A20 zinc finger 7 mutation is associated with early-onset lupus-like disease

A20 is an anti-inflammatory protein that suppresses nuclear factor-κB (NF-κB)-mediated inflammatory gene expression and inhibits cell death. Disruption of A20 function results in defective suppression of the NF-κB pathway, manifesting in diverse autoimmune and autoinflammatory conditions. While autosomal dominant A20 mutations have been identified to cause autoinflammatory disease, recessive A20 mutations causing disease have not been previously described.

We utilized whole exome sequencing to identify the variant of interest. In silico structural modeling as well as immunoprecipitation were used to ascertain A20's interaction with linear ubiquitin, coupled with flow cytometric analysis and western blotting to measure the expression of NF-κB activation markers. We quantified NF-κB pathway activity using NF-κB reporter assay.

Here, we report a novel homozygous mutation in the A20 protein responsible for early-onset lupus-like disease starting at four years of age. We show that the A20 E781K variant, situated in the seventh zinc finger domain of A20, compromises the protein's ability to bind linear ubiquitin, resulting in a functional hypomorph with a reduced capacity to inhibit NF-κB activation and downstream gene expression in HEK293 cells.

Our findings characterize a critical mutation associated with early-onset lupus-like disease in its recessive form and continue to highlight the important role of A20 in maintaining immune homeostasis.