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A zebrafish functional genomics model to investigate the role of human A20
variants in vivo.
Cultrone D, Zammit NW, Self E, Postert B, Han JZR, Bailey J, Warren J, Croucher
DR, Kikuchi K, Bogdanovic O, Chtanova T, Hesselson D, Grey ST
Submitted Externally on 11/10/2020
Volume : Pages
10 : 19085
Germline loss-of-function variation in TNFAIP3, encoding A20, has been
implicated in a wide variety of autoinflammatory and autoimmune conditions, with
acquired somatic missense mutations linked to cancer progression. Furthermore,
human sequence data reveals that the A20 locus contains?~?400 non-synonymous
coding variants, which are largely uncharacterised. The growing number of A20
coding variants with unknown function, but potential clinical impact, poses a
challenge to traditional mouse-based approaches. Here we report the development
of a novel functional genomics approach that utilizes a new A20-deficient
zebrafish (Danio rerio) model to investigate the impact of TNFAIP3 genetic
variants in vivo. A20-deficient zebrafish are hyper-responsive to microbial
immune activation and exhibit spontaneous early lethality. Ectopic addition of
human A20 rescued A20-null zebrafish from lethality, while missense mutations at
two conserved A20 residues, S381A and C243Y, reversed this protective effect.
Ser381 represents a phosphorylation site important for enhancing A20 activity
that is abrogated by its mutation to alanine, or by a causal C243Y mutation that
triggers human autoimmune disease. These data reveal an evolutionarily conserved
role for TNFAIP3 in limiting inflammation in the vertebrate linage and show how
this function is controlled by phosphorylation. They also demonstrate how a
zebrafish functional genomics pipeline can be utilized to investigate the in
vivo significance of medically relevant human TNFAIP3 gene variants.
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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