Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant.

Pediatr Allergy Immunol

Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, IBiS/ Universidad de Sevilla/CSIC, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Seville, Spain.

Published: November 2021

AI Article Synopsis

  • A 10-year-old girl with chronic mucocutaneous candidiasis (a skin and mouth infection) has some mutations in her genes that affect how her immune system works.
  • Scientists studied her gene variants and found one mutation related to STAT1 (which seems okay) and two mutations in another gene called TRAF3IP2 (which is important for signaling in the immune system).
  • These mutations resulted in problems with her immune response, meaning her body couldn't fight off the infection properly.

Article 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 were assessed 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 responses by measuring luciferase induction under a NF-κB-driven reporter system in HEK-293T cells and Gro-α secretion in fibroblasts.

Results: A STAT1 variant (c.1363G>A/p.V455I) was identified by next-generation sequencing and classified as likely non-pathogenic as functional testing revealed normal STAT1 expression and phosphorylation upon IFN-γ. 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 impaired NF-κB activation. Patient's fibroblasts displayed abolished GRO-α secretion upon IL-17A stimulation. 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.

Download full-text PDF

Source
http://dx.doi.org/10.1111/pai.13603DOI Listing

Publication Analysis

Top Keywords

compound heterozygous
12
heterozygous variants
12
chronic mucocutaneous
8
mucocutaneous candidiasis
8
stat1 variant
8
il-17a il-22
8
cd4 cells
8
hek-293t cells
8
gro-α secretion
8
il-17a
5

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!