Isolated Chronic Mucocutaneous Candidiasis due to a Novel Duplication Variant of IL17RC

Noma Kosuke

Tsumura Miyuki

Nguyen Tina

Asano Takaki

Sakura Fumiaki

Tamaura Moe

Imanaka Yusuke

Mizoguchi Yoko

Karakawa Shuhei

Hayakawa Seiichi

Shoji Takayo

Hosokawa Junichi

Izawa Kazushi

Ling Yun

Casanova Jean-Laurent

Puel Anne

Tangye Stuart G.

Ma Cindy S.

Ohara Osamu

Okada Satoshi

Journal of Clinical Immunology

Purpose
Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a 7-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant.
Methods
Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation.
Results
The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of 3 months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient’s SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype.
Conclusions
The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for the diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.

Chronic mucocutaneous candidiasis

isolated CMC

IL-17 immunity

IL-17RC

knockout cell line

inborn error of immunity

英語

Springer

This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1007/s10875-023-01601-9

This is not the published version. Please cite only the published version.

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[DOI] https://doi.org/10.1007/s10875-023-01601-9 ～の異版である

日本学術振興会

Japan Society for the Promotion of Science

[Crossref Funder] https://doi.org/10.13039/501100001691

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