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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 | SH2B3 |
Boaz Palterer gene: SH2B3 was added gene: SH2B3 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature,Expert list Mode of inheritance for gene: SH2B3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SH2B3 were set to 37206266 Phenotypes for gene: SH2B3 were set to Myeloproliferative disorder; Autoimmunity; Hepatosplenomegaly; Thrombosis; Autoimmune thyroiditis; Autoimmune hepatitis; Global developmental delay Penetrance for gene: SH2B3 were set to unknown Review for gene: SH2B3 was set to RED Added comment: Blombery et al. described 2 patients from 2 kindreds, harboring biallelic loss-of-function mutations in the SH2B3 gene. They presented with early-onset developmental delay, hepatosplenomegaly, multi-organ autoimmunity (including autoimmune thyroiditis and hepatitis), bone marrow myeloproliferation, and severe thrombotic complications. The underlying mechanism was validated ex vivo using patient-derived fibroblasts, demonstrating that upon stimulation with various cytokines (including IL-3, GH, GM-CSF, and EPO), the mutant cells exhibited significantly increased phosphorylation and hyperactivation of JAK2 and STAT5 signaling. The phenotype and mechanism were further validated in vivo using CRISPR-Cas9 engineered zebrafish animal models (sh2b3 F0 crispants). These models successfully recreated the myeloproliferative phenotype, presenting with a significantly increased number of macrophages and thrombocytes. Furthermore, rescue and treatment experiments demonstrated that administering the JAK1/2 inhibitor ruxolitinib to the mutant fish successfully intercepted and resolved the myeloproliferative defect. Sources: Literature, Expert list |
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