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<p>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 <i>HLA-B27</i>-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 (<i>IL17RC</i>) mutation was analyzed to investigate its effect on phenotypes. WES was used to identify a known missense mutation, NM_000127.3:c.1019 G &gt; A(p.Arg340His), in the pathogenic gene <i>EXT1</i> that is causal for MO. Moreover, a missense mutation, NM_153461.3:c.1067 C &gt; T(p.Thr356Met), in the <i>IL17RC</i> 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 <i>IL17RA</i>, 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月14日

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

摘要

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.