Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

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作者
Davide Eletto
Siobhan O. Burns
Ivan Angulo
Vincent Plagnol
Kimberly C. Gilmour
Frances Henriquez
James Curtis
Miguel Gaspar
Karolin Nowak
Vanessa Daza-Cajigal
Dinakantha Kumararatne
Rainer Doffinger
Adrian J. Thrasher
Sergey Nejentsev
机构
[1] University of Cambridge,Department of Medicine
[2] University College London Institute of Immunity and Transplantation,Department of Immunology
[3] Royal Free London NHS Foundation Trust,Department of Clinical Biochemistry and Immunology
[4] University College London Genetics Institute,undefined
[5] University College London,undefined
[6] Great Ormond Street Hospital for Children NHS Foundation Trust,undefined
[7] University College London Institute of Child Health,undefined
[8] Addenbrooke’s Hospital,undefined
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Nature Communications | / 7卷
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摘要
Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production. Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of the P733L mutation. Further analyses of the mutant protein reveal a phosphorylation-independent role of JAK1 in signal transduction. These findings clarify JAK1 signalling mechanisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and possibly the immunological surveillance of cancer.
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