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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 | SHARPIN |
Boaz Palterer gene: SHARPIN was added gene: SHARPIN was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature,Expert list Mode of inheritance for gene: SHARPIN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SHARPIN were set to 38609546 Phenotypes for gene: SHARPIN were set to Autoinflammation; Immunodeficiency; Recurrent fever; Dermatitis; Recurrent infections Penetrance for gene: SHARPIN were set to unknown Added comment: Oda et al. described 1 patient from 1 kindred, harboring biallelic loss-of-function mutations in the SHARPIN gene. They presented with distinct clinical autoinflammatory features, recurrent fevers, and subtle immunodeficiency. The underlying mechanism was validated ex vivo using patient-derived cells, demonstrating that the absence of SHARPIN severely destabilizes the linear ubiquitin chain assembly complex (LUBAC), resulting in impaired NF-κB signaling, defective linear ubiquitination, and dysregulated TNF-mediated cell death. The phenotype and mechanism were further validated using in vivo animal models; complete knockout Sharpin-deficient mice (Sharpin cpdm) successfully recreated the severe chronic proliferative dermatitis and multi-organ autoinflammation, confirming the gene's critical role in maintaining immune homeostasis and preventing aberrant cell death. Sources: Literature, Expert list |
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