The following is a summary of “Opposing effects of two gene defects in STX11 and SLP76 on the disease in a patient with an inborn error of immunity,” published in the December 2023 issue of Allergy & Immunology by Mansour, et al.

Inborn errors of immunity are typically monogenic, but the coexistence of a second gene defect can modify disease phenotype and outcome. The study addressed the genetic basis of a patient’s severe clinical manifestations, including bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia leading to death. 

For a study, researchers sought to identify the underlying genetic abnormalities in a patient with a complex clinical presentation.

Genetic analysis was conducted using next-generation sequencing. Protein expression and phosphorylation were assessed through immunoblotting. T-cell proliferation and F-actin levels were studied using flow cytometry.

The patient was found to have two homozygous deletions in STX11 (c.369_{_}370del, c.374_{_}376del; p.V124fs60∗), previously associated with familial hemophagocytic lymphohistiocytosis. Additionally, a novel homozygous missense variant in SLP76 (c.767C>T; p.T256I) was identified, resulting in an approximately 85% decrease in SLP76 levels and impaired T-cell proliferation. Heterozygous family members exhibited approximately 50% decreased SLP76 levels but normal immune function. SLP76-deficient J14 Jurkat cells lacked SLP76 expression, showing decreased extracellular signal-regulated kinase signaling, basal F-actin levels, and polymerization following T-cell receptor stimulation. Reintroduction of T256I mutant SLP76 into J14 cells resulted in low protein expression, abnormal extracellular signal-regulated kinase phosphorylation, and F-actin polymerization after T-cell receptor activation compared to normal expression and function when wild-type SLP76 was reintroduced.

The study unveils a hypomorphic mutation in SLP76 that dampens hyperinflammation caused by STX11 deletion, resulting in a combined immunodeficiency that surpasses the hemophagocytic lymphohistiocytosis phenotype. The case represented the first report of opposing effects from two gene defects on disease manifestation in an individual with an inborn error of immunity.

Source: jacionline.org/article/S0091-6749(23)01018-7/fulltext