Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: MAP4K1

Red List (low evidence)

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

Created: 8 Oct 2026, 6:52 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Recurrent fever; Arthritis; Rash; Arthralgia; Autoimmune disease; Lymphadenopathy; Splenomegaly

Publications

• 40716650