Toggle Main Menu Toggle Search

Open Access padlockePrints

Omenn Syndrome in Two Infants with Different Hypomorphic Variants in Janus Kinase 3

Lookup NU author(s): Dr Christo TsilifisORCiD, Dr Jarmila SpegarovaORCiD, Ross Good, Dr Helen GriffinORCiD, Dr Karin Engelhardt, Professor Sophie Hambleton, Professor Andrew GenneryORCiD

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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

Data Access Statement: The datasets generated during and analysed during the current study are not available for sharing, but the corresponding author may be contacted with queries.


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
207556_Z_17_Z
Wellcome Trust

Share