TRAF3IP2 – Chronic Mucocutaneous Candidiasis

TRAF3 interacting protein 2 (TRAF3IP2) encodes the adaptor ACT1, which is essential for IL-17 receptor–mediated signaling in mucocutaneous antifungal immunity. Biallelic loss‐of‐function in TRAF3IP2 causes autosomal recessive chronic mucocutaneous candidiasis (chronic mucocutaneous candidiasis).

Clinical reports describe an 18-year-old boy from a consanguineous family with recurrent oral candidiasis, pneumonia, bronchiectasis, abnormal dentition (HP:0000164), clubbing, and refractory thrush (HP:0002728, HP:0002841) (PMID:31292894). Two unrelated patients harboring homozygous nonsense variants and one child with compound heterozygous frameshift/missense variants presented with early‐onset mucocutaneous fungal infections and impaired IL-17–driven responses (PMID:33359359; PMID:34289170).

Inheritance is autosomal recessive, supported by consanguinity, absence of disease in heterozygous carriers, and segregation of biallelic truncating alleles in three unrelated families. No additional affected relatives were reported in these pedigrees.

To date, four probands from three independent lineages have been identified: c.559C>T (p.Gln500Ter) (PMID:33359359) and compound c.1335del (p.Lys445AsnfsTer12)/c.1325A>G (p.Asp442Gly) (PMID:34289170). All are predicted or shown to abolish ACT1 function.

Functional assays confirm complete loss of ACT1 protein expression and defective NF-κB activation upon IL-17A/IL-25 stimulation in patient cells, resulting in absent chemokine induction and Th17 impairment concordant with the clinical phenotype (PMID:33359359; PMID:34289170).

Collectively, these data fulfill a moderate level of clinical validity for TRAF3IP2 in chronic mucocutaneous candidiasis, with robust genetic and functional concordance. TRAF3IP2 sequencing is indicated in patients with early‐onset, refractory mucocutaneous candidiasis to guide diagnosis and management.

References

• Journal of clinical immunology • 2019 • Chronic Mucocutaneous Candidiasis in an Adolescent Boy Due to a Novel Mutation in TRAF3IP2. PMID:31292894
• The Journal of allergy and clinical immunology • 2021 • Two patients with chronic mucocutaneous candidiasis caused by TRAF3IP2 deficiency. PMID:33359359
• Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology • 2021 • Biallelic TRAF3IP2 variants causing chronic mucocutaneous candidiasis in a child harboring a STAT1 variant. PMID:34289170

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