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Autosomal recessive deficiency of IL17RC underlies isolated Chronic mucocutaneous candidiasis, characterized by persistent superficial Candida infections without systemic involvement. The syndrome presents with recurrent oral and skin candidiasis beginning in infancy, often without staphylococcal disease. Immunologically, patients exhibit absent cellular responses to IL-17A/F stimulation despite intact upstream signaling.
To date, AR IL17RC deficiency has been described in three unrelated kindreds, each segregating homozygous loss-of-function alleles. The most recent report details a seven-year-old Japanese girl with onset of oral candidiasis at three months carrying a novel homozygous duplication variant, c.1325_1373dup (p.Asp457AlafsTer16) (PMID:37577484; PMID:38129603). Two additional kindreds harboring nonsense variants (c.1132C>T (p.Gln378Ter) and c.199C>T (p.Gln67Ter)) further support allelic heterogeneity.
All reported pathogenic alleles are predicted or shown to abrogate receptor function via premature termination, consistent with a loss-of-function mechanism. Segregation in consanguineous or multiplex families confirms AR inheritance; no affected heterozygotes have been reported. The variant spectrum comprises small duplications and nonsense mutations, each eliminating the critical extracellular or transmembrane domains of IL-17RC.
Comprehensive functional assays established severe impairment of IL-17A signaling. Patient fibroblasts failed to phosphorylate downstream targets and lacked upregulation of IL-17A-responsive genes by flow cytometry, qPCR, RNA-seq, and immunoblotting. CRISPR/Cas9 IL17RC knockout cell lines complemented with WT‐IL17RC restored IL-17A responsiveness, whereas introduction of the c.1325_1373dup allele failed to rescue signaling (PMID:38129603).
No conflicting reports have emerged, and the cellular phenotype directly mirrors human susceptibility to mucocutaneous candidiasis. The scarcity of kindreds limits large-scale genotype–phenotype correlations; however, all variants uniformly result in receptor null alleles.
Collectively, genetic and experimental data establish a moderate clinical validity for IL17RC in chronic mucocutaneous candidiasis. This underscores the diagnostic utility of targeted sequencing and functional assays for patients with persistent mucocutaneous Candida infections. Key Take-home: IL17RC loss-of-function should be considered in infants with isolated chronic mucocutaneous candidiasis for precise molecular diagnosis and potential IL-17 pathway–directed therapies.
Gene–Disease AssociationModerateReported in three unrelated kindreds with autosomal recessive segregation and concordant functional loss-of-function assays ([PMID:37577484]; [PMID:38129603]) Genetic EvidenceModerateThree distinct homozygous loss-of-function IL17RC alleles identified in three probands across unrelated families Functional EvidenceStrongExtensive in vitro assays (flow cytometry, qPCR, RNA-seq, immunoblot) and rescue experiments in IL17RC knockout cells confirm receptor loss-of-function |