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Lookup NU author(s): Dr Christo TsilifisORCiD, Dr Jarmila SpegarovaORCiD, Ross Good, Dr Helen GriffinORCiD, Dr Karin Engelhardt, Professor Sophie HambletonORCiD, Professor Andrew GenneryORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.Biallelic null or hypomorphic variants in JAK3 cause SCID and less frequently Omenn syndrome. We investigated homozygous hypomorphic JAK3 mutations in two patients, and expression and function of a novel JAK3R431P variant in Omenn syndrome. Immunophenotyping of PBMC from the patient with the novel JAK3R431P variant was undertaken, by flow cytometry and Phosflow after stimulation with IL-2, IL-7, and IL-15. JAK3 expression was investigated by Western blotting. We report two patients with homozygous hypomorphic JAK3 variants and clinical features of Omenn syndrome. One patient had a previously described JAK3R775H variant, and the second had a novel JAK3R431P variant. One patient with a novel JAK3R431P variant had normal expression of JAK3 in immortalised EBV-LCL cells but reduced phosphorylation of STAT5 after stimulation with IL-2, IL-7, and IL-15 consistent with impaired kinase activity. These results suggest the JAK3R431P variant to be hypomorphic. Both patients are alive and well after allogeneic haematopoietic stem cell transplantation. They have full donor chimerism, restitution of thymopoiesis and development of appropriate antibody responses following vaccination. We expand the phenotype of hypomorphic JAK3 deficiency and demonstrate the importance of functional testing of novel variants in disease-causing genes.
Author(s): Tsilifis C, Spegarova JS, Good R, Griffin H, Engelhardt KR, Graham S, Hughes S, Arkwright PD, Hambleton S, Gennery AR
Publication type: Article
Publication status: Published
Journal: Journal of Clinical Immunology
Year: 2024
Volume: 44
Issue: 4
Online publication date: 10/04/2024
Acceptance date: 02/04/2024
Date deposited: 18/04/2024
ISSN (print): 0271-9142
ISSN (electronic): 1573-2592
Publisher: Springer
URL: https://doi.org/10.1007/s10875-024-01699-5
DOI: 10.1007/s10875-024-01699-5
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