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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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.
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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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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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DOI: https://doi.org/10.1007/s10875-023-01601-9