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Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice
Spleen Tyrosine Kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, systemic disease such as colitis, arthritis and skin inflammation, and diffuse large B cell lymphomas. The SYK variants...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
2021
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245161/ https://www.ncbi.nlm.nih.gov/pubmed/33782605 http://dx.doi.org/10.1038/s41588-021-00803-4 |
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| author | Wang, Lin Aschenbrenner, Dominik Zeng, Zhiyang Cao, Xiya Mayr, Daniel Mehta, Meera Capitani, Melania Warner, Neil Pan, Jie Wang, Liren Li, Qi Zuo, Tao Cohen-Kedar, Sarit Lu, Jiawei Ardy, Rico Chandra Mulder, Daniel J. Dissanayake, Dilan Peng, Kaiyue Huang, Zhiheng Li, Xiaoqin Wang, Yuesheng Wang, Xiaobing Li, Shuchao Bullers, Samuel Gammage, Anís N. Warnatz, Klaus Schiefer, Ana-Iris Krivan, Gergely Goda, Vera Kahr, Walter H.A. Lemaire, Mathieu Lu, Chien-Yi Siddiqui, Iram Surette, Michael G. Kotlarz, Daniel Engelhardt, Karin R. Griffin, Helen R. Rottapel, Robert Decaluwe, Hélène Laxer, Ronald M. Proietti, Michele Hambleton, Sophie Elcombe, Suzanne Guo, Cong-Hui Grimbacher, Bodo Dotan, Iris Ng, Siew C. Freeman, Spencer A. Snapper, Scott B. Klein, Christoph Boztug, Kaan Huang, Ying Li, Dali Uhlig, Holm H. Muise, Aleixo M. |
| author_facet | Wang, Lin Aschenbrenner, Dominik Zeng, Zhiyang Cao, Xiya Mayr, Daniel Mehta, Meera Capitani, Melania Warner, Neil Pan, Jie Wang, Liren Li, Qi Zuo, Tao Cohen-Kedar, Sarit Lu, Jiawei Ardy, Rico Chandra Mulder, Daniel J. Dissanayake, Dilan Peng, Kaiyue Huang, Zhiheng Li, Xiaoqin Wang, Yuesheng Wang, Xiaobing Li, Shuchao Bullers, Samuel Gammage, Anís N. Warnatz, Klaus Schiefer, Ana-Iris Krivan, Gergely Goda, Vera Kahr, Walter H.A. Lemaire, Mathieu Lu, Chien-Yi Siddiqui, Iram Surette, Michael G. Kotlarz, Daniel Engelhardt, Karin R. Griffin, Helen R. Rottapel, Robert Decaluwe, Hélène Laxer, Ronald M. Proietti, Michele Hambleton, Sophie Elcombe, Suzanne Guo, Cong-Hui Grimbacher, Bodo Dotan, Iris Ng, Siew C. Freeman, Spencer A. Snapper, Scott B. Klein, Christoph Boztug, Kaan Huang, Ying Li, Dali Uhlig, Holm H. Muise, Aleixo M. |
| author_sort | Wang, Lin |
| collection | PubMed |
| description | Spleen Tyrosine Kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, systemic disease such as colitis, arthritis and skin inflammation, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling indicating gain-of-function. A knock-in (SYK(S544Y)) mouse model of a patient variant (p.S550Y) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wildtype mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease. |
| format | Online Article Text |
| id | pubmed-8245161 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2021 |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-82451612021-09-29 Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice Wang, Lin Aschenbrenner, Dominik Zeng, Zhiyang Cao, Xiya Mayr, Daniel Mehta, Meera Capitani, Melania Warner, Neil Pan, Jie Wang, Liren Li, Qi Zuo, Tao Cohen-Kedar, Sarit Lu, Jiawei Ardy, Rico Chandra Mulder, Daniel J. Dissanayake, Dilan Peng, Kaiyue Huang, Zhiheng Li, Xiaoqin Wang, Yuesheng Wang, Xiaobing Li, Shuchao Bullers, Samuel Gammage, Anís N. Warnatz, Klaus Schiefer, Ana-Iris Krivan, Gergely Goda, Vera Kahr, Walter H.A. Lemaire, Mathieu Lu, Chien-Yi Siddiqui, Iram Surette, Michael G. Kotlarz, Daniel Engelhardt, Karin R. Griffin, Helen R. Rottapel, Robert Decaluwe, Hélène Laxer, Ronald M. Proietti, Michele Hambleton, Sophie Elcombe, Suzanne Guo, Cong-Hui Grimbacher, Bodo Dotan, Iris Ng, Siew C. Freeman, Spencer A. Snapper, Scott B. Klein, Christoph Boztug, Kaan Huang, Ying Li, Dali Uhlig, Holm H. Muise, Aleixo M. Nat Genet Article Spleen Tyrosine Kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, systemic disease such as colitis, arthritis and skin inflammation, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling indicating gain-of-function. A knock-in (SYK(S544Y)) mouse model of a patient variant (p.S550Y) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wildtype mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease. 2021-03-29 2021-04 /pmc/articles/PMC8245161/ /pubmed/33782605 http://dx.doi.org/10.1038/s41588-021-00803-4 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
| spellingShingle | Article Wang, Lin Aschenbrenner, Dominik Zeng, Zhiyang Cao, Xiya Mayr, Daniel Mehta, Meera Capitani, Melania Warner, Neil Pan, Jie Wang, Liren Li, Qi Zuo, Tao Cohen-Kedar, Sarit Lu, Jiawei Ardy, Rico Chandra Mulder, Daniel J. Dissanayake, Dilan Peng, Kaiyue Huang, Zhiheng Li, Xiaoqin Wang, Yuesheng Wang, Xiaobing Li, Shuchao Bullers, Samuel Gammage, Anís N. Warnatz, Klaus Schiefer, Ana-Iris Krivan, Gergely Goda, Vera Kahr, Walter H.A. Lemaire, Mathieu Lu, Chien-Yi Siddiqui, Iram Surette, Michael G. Kotlarz, Daniel Engelhardt, Karin R. Griffin, Helen R. Rottapel, Robert Decaluwe, Hélène Laxer, Ronald M. Proietti, Michele Hambleton, Sophie Elcombe, Suzanne Guo, Cong-Hui Grimbacher, Bodo Dotan, Iris Ng, Siew C. Freeman, Spencer A. Snapper, Scott B. Klein, Christoph Boztug, Kaan Huang, Ying Li, Dali Uhlig, Holm H. Muise, Aleixo M. Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice |
| title | Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice |
| title_full | Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice |
| title_fullStr | Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice |
| title_full_unstemmed | Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice |
| title_short | Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice |
| title_sort | gain-of-function variants in syk cause immune dysregulation and systemic inflammation in humans and mice |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245161/ https://www.ncbi.nlm.nih.gov/pubmed/33782605 http://dx.doi.org/10.1038/s41588-021-00803-4 |
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