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Identification of an IL17RC missense variant in a Chinese family with multiple osteochondromas and ankylosing spondylitis

Journal of Human Genetics volume 70, pages 557–564 (2025)Cite this article

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Abstract

Ankylosing spondylitis (AS) is a chronic and progressive inflammatory arthritis involving disorders of both the immune and skeletal systems. Multiple osteochondromas (MO) is a rare skeletal disorder with a variety of clinical manifestations characterized by multiple benign exostoses. Here, we investigate a Chinese family with HLA-B27-negative AS complicated with MO. Whole-exome sequencing (WES) and Sanger sequencing were used to screen and identify the pathogenic gene. In vitro functional analysis was performed, and a pathogenesis-associated interleukin (IL)-17 receptor C (IL17RC) mutation was analyzed to investigate its effect on phenotypes. WES was used to identify a known missense mutation, NM_000127.3:c.1019 G > A(p.Arg340His), in the pathogenic gene EXT1 that is causal for MO. Moreover, a missense mutation, NM_153461.3:c.1067 C > T(p.Thr356Met), in the IL17RC gene was identified as potentially responsible for AS or spondyloarthritis symptoms in this family. In vitro over-expression of mutant IL17RC decreased its expression and increased the expression of IL17RA, consistent with the expression of these two genes in patients. Mechanistically, mutant IL17RC enhanced the activation of the NF-κB pathway. This study increases our understanding of the pathogenesis and progression of these diseases. Our findings broaden the risk factors in non-HLA-B genes associated with the NF-κB pathway in AS.

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Fig. 1: Pedigree and clinical phenotypes of the family.
Fig. 2: Mutation screening analysis.
Fig. 3: In silico analysis.
Fig. 4: Effect of mutation on IL17RC function.
Fig. 5: Subcellular localization of Flag-tag wild-type and mutant IL17RC in HEK293T cells showed similar distributions.

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Data availability

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

References

  1. Liu L, Yuan Y, Zhang S, Xu J, Zou J. Osteoimmunological insights into the pathogenesis of ankylosing spondylitis. J Cell Physiol. 2021;236:6090–100.

  2. Dakwar E, Reddy J, Vale FL, Uribe JS. A review of the pathogenesis of ankylosing spondylitis. Neurosurg Focus. 2008;24:E2.

    Article  PubMed  Google Scholar 

  3. Wu F, Han X, Liu J, Zhang Z, Yan K, Wang B, et al. An ankylosing spondylitis risk variant alters osteoclast differentiation. Rheumatology. 2023;62:1980–87.

    Article  PubMed  CAS  Google Scholar 

  4. Akkoç N, Yarkan H, Kenar G, Khan MA. Ankylosing spondylitis: HLA-B*27-Positive versus HLA-B*27-negative disease. Curr Rheumatol Rep. 2017;19:26.

    Article  PubMed  Google Scholar 

  5. Ben-Shabat N, Shabat A, Watad A, Kridin K, Bragazzi NL, Mcgonagle D, et al. Mortality in ankylosing spondylitis according to treatment: a nationwide retrospective cohort study of 5,900 patients from Israel. Arthritis Care Res. 2022;74:1614–22.

    Article  CAS  Google Scholar 

  6. Zhu W, He X, Cheng K, Zhang L, Chen D, Wang X, et al. Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res. 2019;7:22.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Khan MA, Yong SB, Wei JC. Ankylosing spondylitis: history, epidemiology, and HLA-B27. Int J Rheum Dis. 2023;26:413–14.

    Article  PubMed  Google Scholar 

  8. Reveille JD, Sims AM, Danoy P, Evans DM, Leo P, Pointon JJ, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010;42:123–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Sode J, Bank S, Vogel U, Andersen PS, Sorensen SB, Bojesen AB, et al. Genetically determined high activities of the TNF-alpha, IL23/IL17, and NFkB pathways were associated with increased risk of ankylosing spondylitis. BMC Med Genet. 2018;19:165.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Klavdianou K, Tsiami S, Baraliakos X. New developments in ankylosing spondylitis-status in 2021. Rheumatology. 2021;60:vi29–37.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kim S, Lee C, Choi S, Kim M, Jung ST. A genotype-phenotype study of multiple hereditary exostoses in forty-three patients. J Clin Med. 2022;11:3703.

  12. Phan AQ, Pacifici M, Esko JD. Advances in the pathogenesis and possible treatments for multiple hereditary exostoses from the 2016 international MHE conference. Connective Tissue Res. 2018;59:85–98.

  13. Jurik AG. Multiple hereditary exostoses and enchondromatosis. Best Pract Res Clin Rheumatol. 2020;34:101505.

    Article  PubMed  Google Scholar 

  14. Stieber JR, Dormans JP. Manifestations of hereditary multiple exostoses. J Am Acad Orthop Surg. 2005;13:110–20.

  15. Bukowska-Olech E, Trzebiatowska W, Czech W, Drzymała O, Frąk P, Klarowski F, et al. Hereditary multiple exostoses-a review of the molecular background, diagnostics, and potential therapeutic strategies. Front Genet. 2021;12:759129.

  16. Al-Zayed Z, Al-Rijjal RA, Al-Ghofaili L, Binessa HA, Pant R, Alrabiah A, et al. Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses. Orphan J Rare Dis. 2021;16:100.

  17. Alexandrou A, Salameh N, Papaevripidou I, Nicolaou N, Myrianthopoulos P, Ketoni A, et al. Hereditary multiple exostoses caused by a chromosomal inversion removing part of EXT1 gene. Mol Cytogenet. 2023;16. https://doi.org/10.1186/s13039-023-00638-0.

  18. Yang C, Zhang R, Lin H, Wang H. Insights into the molecular regulatory network of pathomechanisms in osteochondroma. J Cell Biochem. 2019;120:16362–69.

    Article  PubMed  CAS  Google Scholar 

  19. Pacifici M. Hereditary multiple exostoses: are there new plausible treatment strategies? Expert Opin Orphan Drugs. 2018;6:385–91.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Lin J, Wu Z, Zheng Y, Shen Z, Gan Z, Ma S, et al. Plasma-derived exosomal miRNA profiles reveal potential epigenetic pathogenesis of premature ovarian failure. Hum Genet. 2024;143:1021–34.

    Article  PubMed  CAS  Google Scholar 

  21. Liao HT, Tsai CY. Cytokines and regulatory T cells in ankylosing spondylitis. Bone Jt Res. 2023;12:133–37. https://doi.org/10.1302/2046-3758.122.BJR-2022-0195.R1.

    Article  Google Scholar 

  22. Robinson PC, van der Linden S, Khan MA, Taylor WJ. Axial spondyloarthritis: concept, construct, classification and implications for therapy. Nat Rev Rheumatol. 2021;17:109–18. https://doi.org/10.1038/s41584-020-00552-4.

    Article  PubMed  Google Scholar 

  23. Dougados M, Sepriano A, Molto A, van Lunteren M, Ramiro S, de Hooge M, et al. Sacroiliac radiographic progression in recent onset axial spondyloarthritis: the 5-year data of the DESIR cohort. Ann Rheum Dis. 2017;76:1823–28. https://doi.org/10.1136/annrheumdis-2017-211596.

    Article  PubMed  Google Scholar 

  24. Tavasolian F, Lively S, Pastrello C, Tang M, Lim M, Pacheco A, et al. Proteomic and genomic profiling of plasma exosomes from patients with ankylosing spondylitis. Ann Rheum Dis. 2023;82:1429–43. https://doi.org/10.1136/ard-2022-223791.

    Article  PubMed  CAS  Google Scholar 

  25. Wang R, Maksymowych WP. Targeting the Interleukin-23/Interleukin-17 inflammatory pathway: successes and failures in the treatment of axial spondyloarthritis. Front Immunol. 2021;12:715510. https://doi.org/10.3389/fimmu.2021.715510.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Ward MM, Deodhar A, Gensler LS, Dubreuil M, Yu D, Khan MA, et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Rheumatol. 2019;71:1599–613. https://doi.org/10.1002/art.41042.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tsukazaki H, Kaito T. The role of the IL-23/IL-17 pathway in the pathogenesis of spondyloarthritis. Int J Mol Sci. 2020;21. https://doi.org/10.3390/ijms21176401.

  28. Mimpen JY, Baldwin MJ, Cribbs AP, Philpott M, Carr AJ, Dakin SG, et al. Interleukin-17A Causes Osteoarthritis-Like Transcriptional Changes in Human Osteoarthritis-Derived Chondrocytes and Synovial Fibroblasts In Vitro. Front Immunol. 2021;12:676173. https://doi.org/10.3389/fimmu.2021.676173.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Wang P, Liu X, Kong C, Liu X, Teng Z, Ma Y, et al. Potential role of the IL17RC gene in the thoracic ossification of the posterior longitudinal ligament. Int J Mol Med. 2019;43:2005–14. https://doi.org/10.3892/ijmm.2019.4130.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med. 2006;203:2673–82. https://doi.org/10.1084/jem.20061775.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Goepfert A, Lehmann S, Blank J, Kolbinger F, Rondeau J. Structural analysis reveals that the cytokine IL-17F forms a homodimeric complex with receptor IL-17RC to Drive IL-17RA-Independent Signaling. Immunity. 2020;52:499–512. https://doi.org/10.1016/j.immuni.2020.02.004.

    Article  PubMed  CAS  Google Scholar 

  32. Wright JF, Bennett F, Li B, Brooks J, Luxenberg DP, Whitters MJ, et al. The human IL-17F/IL-17A heterodimeric cytokine signals through the IL-17RA/IL-17RC receptor complex. J Immunol. 2008;181:2799–805. https://doi.org/10.4049/jimmunol.181.4.2799.

    Article  PubMed  CAS  Google Scholar 

  33. Aghaei H, Farhadi E, Akhtari M, Shahba S, Mostafaei S, Jamshidi A, et al. Copy number variation of IL17RA gene and its association with the ankylosing spondylitis risk in Iranian patients: a case-control study. BMC Med Genet. 2020;21:147. https://doi.org/10.1186/s12881-020-01078-y.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Ho AW, Gaffen SL. IL-17RC: a partner in IL-17 signaling and beyond. Semin Immunopathol. 2010;32:33–42. https://doi.org/10.1007/s00281-009-0185-0.

    Article  PubMed  CAS  Google Scholar 

  35. Mohaidat Z, Bodoor K, Almomani R, Alorjani M, Awwad MA, Bany-Khalaf A, et al. Hereditary multiple osteochondromas in Jordanian patients: mutational and immunohistochemical analysis of EXT1 and EXT2 genes. Oncol Lett. 2021;21:151 https://doi.org/10.3892/ol.2020.12412.

    Article  PubMed  CAS  Google Scholar 

  36. Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F, et al. Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am J Hum Genet. 1998;62:346–54. https://doi.org/10.1086/301726.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Sfar S, Abid A, Mahfoudh W, Ouragini H, Ouechtati F, Abdelhak S, et al. Genetic analysis of hereditary multiple exostoses in Tunisian families: a novel frame-shift mutation in the EXT1 gene. Mol Biol Rep. 2009;36:661–67. https://doi.org/10.1007/s11033-008-9226-3.

    Article  PubMed  CAS  Google Scholar 

  38. Knudson AJ. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68:820–23. https://doi.org/10.1073/pnas.68.4.820.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Pacifici M. The pathogenic roles of heparan sulfate deficiency in hereditary multiple exostoses. Matrix Biol. 2018;71-72:28–39. https://doi.org/10.1016/j.matbio.2017.12.011.

    Article  PubMed  CAS  Google Scholar 

  40. Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423:332–36. https://doi.org/10.1038/nature01657.

    Article  PubMed  CAS  Google Scholar 

  41. Huegel J, Sgariglia F, Enomoto-Iwamoto M, Koyama E, Dormans JP, Pacifici M. Heparan sulfate in skeletal development, growth, and pathology: the case of hereditary multiple exostoses. Dev Dyn. 2013;242:1021–32. https://doi.org/10.1002/dvdy.24010.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank the patients and their family members for consenting to this research.

Funding

This work was supported by National Natural Science Foundation of China (32170617, 32370649, 82302078), National Key S&T Special Projects (2022YFC2703303), Natural Science Foundation of Guangdong Province of China (2024A1515012899, 2022A1515110438).

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  1. These authors contributed equally: Yingchun Zheng, Xuewu Wei.

Authors and Affiliations

  1. Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Yingchun Zheng, Xuewu Wei, Zhongzhi Gan, Mingming Zhang, Zongrui Shen, Shunfei Ma, Yihao Huang, Fei He & Fu Xiong

  2. Department of Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

    Yingchun Zheng

  3. Clinical laboratory, Dongguan Dongcheng Hospital, Dongguan, China

    Xuewu Wei

  4. Department of Orthopedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Jian Wang

  5. Department of Fetal Medicine and Prenatal Diagnosis, Zhujiang Hospital, Southern Medical University, Guangzhou, China

    Fu Xiong

  6. Key Laboratory of Reproductive Health Diseases Research and Translation (Hainan Medical University), Ministry of Education, Haikou, China

    Fu Xiong

  7. Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, China

    Fu Xiong

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Contributions

YC Zheng, XW Wei, J Wang and F Xiong were responsible for experimentation and wrote the manuscript. ZZ Gan, MM Zhang and ZR Shen assisted with the data collection and analyzed. SF Ma, YH Huang and F He contributed to the experimentation. J Wang and F Xiong were responsible for study design and the conduct of the study. All authors contributed to this article and determined the final version.

Corresponding authors

Correspondence to Jian Wang or Fu Xiong.

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The authors declare no competing interests.

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Approval was obtained from the Ethics Committee of Nanfang Hospital, an affiliate of Southern Medical University. The procedures used in this study adhere to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants or their guardians.

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Zheng, Y., Wei, X., Gan, Z. et al. Identification of an IL17RC missense variant in a Chinese family with multiple osteochondromas and ankylosing spondylitis. J Hum Genet 70, 557–564 (2025). https://doi.org/10.1038/s10038-025-01383-5

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