Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome
Abstract Background and objectives The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants. Methods RNA sequencing analyses were used to detect transcripto...
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Arthritis Research & Therapy |
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| Online Access: | https://doi.org/10.1186/s13075-024-03286-w |
| _version_ | 1797273709172490240 |
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| author | Jingyuan Zhang Yi Luo Bingxuan Wu Xin Huang Mengzhu Zhao Na Wu Junke Miao Ji Li Lei Zhu Di Wu Min Shen |
| author_facet | Jingyuan Zhang Yi Luo Bingxuan Wu Xin Huang Mengzhu Zhao Na Wu Junke Miao Ji Li Lei Zhu Di Wu Min Shen |
| author_sort | Jingyuan Zhang |
| collection | DOAJ |
| description | Abstract Background and objectives The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants. Methods RNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines. Results Transcriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement. Conclusion Overproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS. |
| first_indexed | 2024-03-07T14:48:09Z |
| format | Article |
| id | doaj.art-ed9935d638e1469ca9bde11edc71d39e |
| institution | Directory Open Access Journal |
| issn | 1478-6362 |
| language | English |
| last_indexed | 2024-03-07T14:48:09Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Arthritis Research & Therapy |
| spelling | doaj.art-ed9935d638e1469ca9bde11edc71d39e2024-03-05T19:51:59ZengBMCArthritis Research & Therapy1478-63622024-02-0126111510.1186/s13075-024-03286-wIdentifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndromeJingyuan Zhang0Yi Luo1Bingxuan Wu2Xin Huang3Mengzhu Zhao4Na Wu5Junke Miao6Ji Li7Lei Zhu8Di Wu9Min Shen10Department of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationDepartment of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationDepartment of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationDepartment of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationDepartment of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationDepartment of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationDepartment of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationDepartment of Gastroenterology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical CollegeDepartment of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; State Key Laboratory of Complex Severe and Rare Diseases; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationDepartment of Rare Diseases, Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences & Peking Union Medical College; State Key Laboratory of Complex Severe and Rare Diseases, PUMCH; Department of Rheumatology and Clinical Immunology, PUMCH; National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology; Key Laboratory of Rheumatology and Clinical Immunology, Ministry of EducationAbstract Background and objectives The study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants. Methods RNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines. Results Transcriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement. Conclusion Overproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.https://doi.org/10.1186/s13075-024-03286-wYao syndromeNucleotide-binding oligomerization domain containing 2 (NOD2)PathogenesisSystemic autoinflammatory diseases |
| spellingShingle | Jingyuan Zhang Yi Luo Bingxuan Wu Xin Huang Mengzhu Zhao Na Wu Junke Miao Ji Li Lei Zhu Di Wu Min Shen Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome Arthritis Research & Therapy Yao syndrome Nucleotide-binding oligomerization domain containing 2 (NOD2) Pathogenesis Systemic autoinflammatory diseases |
| title | Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome |
| title_full | Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome |
| title_fullStr | Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome |
| title_full_unstemmed | Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome |
| title_short | Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome |
| title_sort | identifying functional dysregulation of nod2 variant q902k in patients with yao syndrome |
| topic | Yao syndrome Nucleotide-binding oligomerization domain containing 2 (NOD2) Pathogenesis Systemic autoinflammatory diseases |
| url | https://doi.org/10.1186/s13075-024-03286-w |
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