The opposing effects of two gene defects in STX11 and SLP76 on the disease in a patient with an inborn error of immunity

Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect. We sought to identify the genetic basis of the disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pn...

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Bibliographic Details
Published in:Journal of allergy and clinical immunology 2023-12, Vol.152 (6), p.1597-1606
Main Authors: Mansour, Rana, El-Hassan, Rana, El-Orfali, Youmna, Saidu, Adam, Al-Kalamouni, Habib, Chen, Qian, Benamar, Mehdi, Dbaibo, Ghassan, Hanna-Wakim, Rima, Chatila, Talal A., Massaad, Michel J.
Format: Article
Language:English
Subjects:
Actins
combined immunodeficiency
Extracellular Signal-Regulated MAP Kinases
hemophagocytic lymphohistiocytosis
Humans
Inborn errors of immunity
Lymphohistiocytosis, Hemophagocytic - genetics
Mutation
Qa-SNARE Proteins - genetics
Receptors, Antigen, T-Cell - genetics
Signal Transduction
SLP76
STX11
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Summary:Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect. We sought to identify the genetic basis of the disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia that resulted in death. Genetic analysis was done using next-generation sequencing. Protein expression and phosphorylation were determined by immunoblotting. T-cell proliferation and F-actin levels were studied by flow cytometry. The patient harbored 2 homozygous deletions in STX11 (c.369_370del, c.374_376del; p.V124fs60∗) previously associated with familial hemophagocytic lymphohistiocytosis and a novel homozygous missense variant in SLP76 (c.767C>T; p.T256I) that resulted in an approximately 85% decrease in SLP76 levels and absent T-cell proliferation. The patient’s heterozygous family members showed an approximately 50% decrease in SLP76 levels but normal immune function. SLP76-deficient J14 Jurkat cells did not express SLP76 and had decreased extracellular signal-regulated kinase signaling, basal F-actin levels, and polymerization following T-cell receptor stimulation. Reconstitution of J14 cells with T256I mutant SLP76 resulted in low protein expression and abnormal extracellular signal-regulated kinase phosphorylation and F-actin polymerization after T-cell receptor activation compared with normal expression and J14 function when wild-type SLP76 was introduced. The hypomorphic mutation in SLP76 tones down the hyperinflammation due to STX11 deletion, resulting in a combined immunodeficiency that overshadows the hemophagocytic lymphohistiocytosis phenotype. To our knowledge, this study represents the first report of the opposing effects of 2 gene defects on the disease in a patient with an inborn error of immunity.
ISSN:0091-6749
1097-6825
DOI:10.1016/j.jaci.2023.08.005