TRAF3IP2 variants in a child with chronic mucocutaneous candidiasis-
keeping an open mind!
Abstract
Background: Inherited chronic mucocutaneous candidiasis (CMC) is often
caused by inborn errors of immunity, impairing the response to, or the
production of IL-17A and IL-17F. About half of the cases carry STAT1
gain-of-function (GOF) mutations. Only few patients have been reported
with mutations of TRAF3IP2, a gene encoding the adaptor ACT1 essential
for IL-17-receptor(R) -signaling. We investigated a 10-year-old girl
with CMC, carrying a heterozygous variant of STAT1 and compound
heterozygous variants of TRAF3IP2. Methods: By flow cytometry STAT1
levels and phosphorylation (CD14+) as well as IL-17A-, IL-22-, IFN-γ-
and IL-4-production (memory CD4+ T cells) were determined. ACT1
expression and binding to IL-17RA by western blot and
co-immunoprecipitation in HEK-293T cells transfected with plasmids
encoding wild-type or mutant HA-tagged ACT1 and Flag-IL-17RA. We
evaluated IL-17A response using an NF-κB-driven luciferase reporter
system in HEK-293T cells, and by measuring GRO-α secretion by
fibroblasts. Results: A likely non-pathogenic STAT1 variant
(c.1363G>A/p.V455I) was identified by next generation
sequencing., STAT1 expression and phosphorylation upon IFN- were
normal. We also found compound heterozygous variants
(c.1325A>G/p.D451G and c.1335delA/p.K454fs11*) of TRAF3IP2.
By overexpression, despite normal protein expression, and impaired
(K454fs11*) or normal (D451G) interaction with IL-17RA, both mutant
alleles resulted in an impaired NF-κB-activation. Patient’s fibroblasts
displayed abolished GRO-α secretion upon IL-17A. Finally, ex vivo CD4+ T
cells showed increased IL-17A, IL-22, and IL-4, and normal-low IFN-γ
expression upon stimulation. Conclusion: We identify novel compound
heterozygous variants of TRAFP3IP2 causing autosomal recessive ACT1
deficiency in a child with CMC, and provide a review of the current
literature.