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

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Abstract

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.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CMC:

Chronic mucocutaneous candidiasis

AD:

Autosomal dominant

AR:

Autosomal recessive

IL:

Interleukin

Th:

T helper

Tfh:

T follicular helper

IEI:

Inborn errors of immunity

NGS :

Next generation sequencing

WT:

Wild-type

SEFIR:

Similar expression to fibroblast growth factor genes and IL-17R

pLOF:

Predicted to be loss-of-function

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Acknowledgements

We thank the patient and her family for their sincere efforts in cooperating with this study. We also thank Menno van Zelm and Hirokazu Kanegane for help in the breakpoint analysis of the mechanism of the duplication variant and Masaki Takazawa for technical assistance. The sequence analysis and the single cell sorting were supported by the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University.

Funding

SO is supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant numbers: 19H03620, 22H03041, 18KK0228, and 22KK0113) and the Japan Agency for Medical Research and Development (AMED) (grant number: JP23ek0109623, JP22ek0109480). MT is supported by MEXT/JSPS KAKENHI (grant numbers: 22K15921) JLC is supported by the National Institutes of Health (grant numbers: R01AI127564). SGT and CSM are supported by Investigator Grants awarded by the National Health and Medical Research Council of Australia and project grants from the Allergy & Immunology Foundation of Australia, and the Job Research Foundation. AP is supported by the Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence (ANR-10-LABX-62-IBEID), the French National Research Agency (ANR) (grant no. GENCMCD-ANR-11-BSV3-005-01, no. HGDIFD-ANR-14-CE15-0006-01, no. EURO-CMC-ANR-14-RARE-0005-02), and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (grant no. U01AI109697 and no. R01AI127564).

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Authors and Affiliations

  1. Department of Pediatrics, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Kosuke Noma, Miyuki Tsumura, Takaki Asano, Fumiaki Sakura, Moe Tamaura, Yusuke Imanaka, Yoko Mizoguchi, Shuhei Karakawa, Seiichi Hayakawa & Satoshi Okada

  2. Immunology Program, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    Tina Nguyen, Stuart G. Tangye & Cindy S. Ma

  3. School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, NSW, Australia

    Tina Nguyen, Stuart G. Tangye & Cindy S. Ma

  4. Division of Pediatric Infectious Diseases, Shizuoka Children’s Hospital, Shizuoka, Japan

    Takayo Shoji

  5. Kazusa DNA Research Institute, Kisarazu, Chiba, Japan

    Junichi Hosokawa & Osamu Ohara

  6. Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Kazushi Izawa

  7. Department of Infectious Disease, Shanghai Public Health Clinical Center, Shanghai, China

    Yun Ling

  8. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France

    Jean-Laurent Casanova & Anne Puel

  9. University of Paris Cité, Imagine Institute, Paris, France

    Jean-Laurent Casanova & Anne Puel

  10. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA

    Jean-Laurent Casanova & Anne Puel

  11. Howard Hughes Medical Institute, New York, NY, USA

    Jean-Laurent Casanova

  12. Department of Pediatrics, Necker Hospital for Sick Children, Paris, France

    Jean-Laurent Casanova

Authors
  1. Kosuke Noma
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  2. Miyuki Tsumura
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Contributions

SO designed and supervised the study. KN wrote the manuscript with support from TA, JLC, AP, SGT, and SO. TS, KI, MT, YI, YM, SK, SH, and YL contributed to sample preparation and provision of clinical information. KN, MT, and TN carried out the experiments. CSM designed and supervised experiments and analyzing data. FS, JH, and OO analyzed the data. All authors contributed to manuscript preparation, read, and approved the final manuscript.

Corresponding author

Correspondence to Satoshi Okada.

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Ethics Approval

This study was approved by the Ethics Committee/Internal Review Board of Hiroshima University. All experiments were carried out with adherence to the Declaration of Helsinki.

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Written informed consent was obtained from the patient’s parent.

Consent for Publication

Consent to submission of the case report to the journal was obtained from the patient’s parent.

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The authors declare no competing interests.

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Noma, K., Tsumura, M., Nguyen, T. et al. Isolated Chronic Mucocutaneous Candidiasis due to a Novel Duplication Variant of IL17RC. J Clin Immunol 44, 18 (2024). https://doi.org/10.1007/s10875-023-01601-9

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