Nat Genetics | Huang Ying/Li Dali and others identify gain-of-function mutations in SYK gene that cause human immune disorders

Editor | Xispleen Tyrosine Kinase (SYK) is a member of the Src family of non-receptor tyrosine kinases.
It is widely expressed in immune cells and is directly related to surface receptors such as B cell receptors and Fcγ receptors.
Signal transduction pathway.

Phosphorylation of SYK can lead to the activation of downstream signaling pathways including PI3K/Akt, Ras/ERK, PLCγ/NFAT, Vav-1/Rac, and IKK/NFκB.

SYK plays an important role in a variety of auto-inflammatory and immune-related diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), allergic asthma and rhinitis, idiopathic thrombocytopenic purpura, etc.
.

Its small molecule inhibitor R406 has also entered clinical trials for the treatment of diseases such as arthritis and idiopathic thrombocytopenic purpura.

Studies have shown that knocking out the Syk gene in mice will lead to embryonic death, and the lack of Syk in hematopoietic stem cells will reduce the differentiation of osteoclasts and play a certain protective effect on autoantibody-induced arthritis, but there has been no clinical practice.
Discover whether SYK mutations can cause human diseases.

 On March 29, 2021, Huang Ying's research team from the Pediatric Hospital of Fudan University, Li Dali's research team from East China Normal University, and Aleixo M.
Muise's research team from The Hospital for Sick Children in Toronto, Canada jointly published an online publication in Nature Genetics.
A research paper entitled "Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice".The study revealed that gain-of-function mutations in the SYK gene can cause immune disorders and systemic inflammation in humans and mice, and explained the relevant molecular mechanisms; through various interventions in animal models, it was verified that the treatment of this The disease strategy lays the foundation for the clinical treatment of immune disorders-related diseases caused by SYK gain-of-function mutations.

 In 2015, the Children's Inflammatory Bowel Disease Research Center of the Children's Hospital of Fudan University, Shanghai, found a case of a child with multiple systemic lesions, manifested as diarrhea, skin rash, perianal fistula, and repeated lung infections within 2 weeks after birth.
Symptoms such as arthritis appeared at the age of 17 months.

CD8+ T cells, TH17 and TH1 cells in the patient’s peripheral blood expanded, and the levels of inflammatory cytokines and chemokines increased significantly.

Whole-exome sequencing revealed that the patient had a heterozygous mutation at position 1649 of C>A in the SYK gene, which caused the 550 amino acid to be changed from serine (Ser) to tyrosine (Tyr) (c.
1649C>A, p.
S550Y).

Studies have found that this mutation leads to a significant increase in the level of phosphorylated SYK protein in the active form, and the corresponding downstream signaling pathways are widely activated.

However, the parents of the child are very healthy and do not carry the SYK mutation.
Therefore, the research team speculates that this is most likely a new gain-of-function mutation that causes immune disorders in humans, but it is difficult for a single patient to form strong evidence.

In order to confirm that the mutation is a pathogenic mutation, on the one hand, the project team started international cooperation, hoping to find more patients of the same kind worldwide, on the other hand, the project team used CRISPR/Cas9 technology to quickly construct a simulated patient S550Y point mutation ( Among mice, S544Y) mouse model.

Fortunately, heterozygous point mutant mice began to show spontaneous arthritis symptoms at the ankle joint at the age of five weeks, which were specifically manifested as joint swelling, dyskinesia, infiltration and erosion of immune cells in the onset of joints, and highly activated osteoclasts, resulting in severe bone Erosion, and the symptoms gradually intensify with age, and similar joint disease occurs in the spine.

Mutant mice also have similar defects in the maturation and differentiation of immune cells and patients, which strongly proves that SYK point mutations are the cause of immune disorders in patients.

The phenotype and etiology of the SYK-Ser544Tyr mouse model have been found, so are there any potential treatment strategies? Since SYK is an important treatment target for arthritis, there are already specific inhibitors in clinical research.

After drug intervention with SYK inhibitors on diseased mice, the ankle joint thickness and clinical arthritis scores of mice were significantly improved compared with the untreated group.

Since SYK is mainly expressed in immune cells, the project team has transplanted bone marrow cells from wild-type mice into SYK point mutant mice and found that it can completely cure arthritis and other phenotypes, suggesting that allogeneic hematopoietic stem cell transplantation may benefit patients.
beneficial.

At the same time, new progress has been made in clinical practice.
After the unremitting efforts of 55 researchers in nine countries, five other patients were found to have mutations at different sites of the SYK gene.

These patients all have immunodeficiency and varying degrees of inflammation of the intestines, skin, joints, liver, and nervous system.

As evidenced by the study of mouse bone marrow transplantation, Canadian patients are considering the strategy of bone marrow transplantation to treat this rare disease.

 Overall, this research work has determined for the first time that SYK gain-of-function mutations can lead to human immune disorders-related diseases, and deepen people’s understanding of the function of SYK.
At the same time, a mouse model of spontaneous arthritis has been obtained.
This is likely to be the first reported model that simulates spontaneous arthritis caused by human mutations, and will provide a reliable experimental animal model for the study of the mechanism of arthritis, the evaluation of drug effects, and precise gene therapy.

 Professor Huang Ying from the Department of Gastroenterology, Pediatric Hospital of Fudan University, Professor Li Dali from the School of Life Sciences, East China Normal University, and Professor Aleixo Muise from the Hospital for Sick Children Hospital of the University of Toronto are the corresponding authors of the paper.

Dr.
Wang Lin from the Department of Gastroenterology, Pediatric Hospital of Fudan University, Dominik Aschenbrenner, postdoctoral fellow at John Radcliffe Hospital, Oxford University, and Dr.
Zeng Zhiyang from the School of Life Sciences, East China Normal University are the co-first authors of this article.  Original link: Reprinting Instructions [Non-original articles] The copyright of this article belongs to the author of the article.
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