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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.109 | MAP4K1 |
Boaz Palterer gene: MAP4K1 was added gene: MAP4K1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: MAP4K1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAP4K1 were set to 40716650 Phenotypes for gene: MAP4K1 were set to Recurrent fever; Arthritis; Rash; Arthralgia; Autoimmune disease; Lymphadenopathy; Splenomegaly Penetrance for gene: MAP4K1 were set to unknown Review for gene: MAP4K1 was set to RED Added comment: Kaustio et al. described multiple patients from two kindreds harboring heterozygous loss-of-function mutations in the MAP4K1 gene. They presented with recurrent fevers, systemic inflammatory symptoms (including an atypical Still disease/Kawasaki-like presentation), inflammatory arthritis, rash, arthralgia, and features of immune dysregulation. The underlying mechanism and phenotype were validated ex vivo and in vitro using patient-derived primary T cells and CRISPR-Cas9-engineered primary human T cells, demonstrating reduced HPK1 protein expression, defective SLP-76 phosphorylation at Ser376, hyperresponsiveness to T-cell receptor stimulation, and elevated secretion of proinflammatory cytokines (notably IFN-γ and TNF). The hyperactive T-cell phenotype was successfully recreated with CRISPR-Cas9 knockout of MAP4K1 in primary human T cells and was partially reversed following targeted genetic rescue/correction of the variant. Sources: Literature |
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