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DOI 10.1038/s41588-021-00803-4

Медицинская библиотека · Nature genetics · 2021

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, Genomics England Research Consortium, 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

СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод в очереди

Аннотация

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, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.

Для цитирования: 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, Genomics England Research Consortium, 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.. Nature genetics. 2021. DOI: 10.1038/s41588-021-00803-4.

Предметные рубрики MeSH

AdultAnimalsArthritisBase SequenceBone Marrow TransplantationColitisDermatitisFamilyFemaleGene ExpressionGene Knock-In TechniquesHumansInfantLymphoma, Large B-Cell, DiffuseMaleMiceMice, KnockoutMiddle AgedMutationPedigreeProtein Kinase InhibitorsSyk Kinase
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