Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

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 and Sergey Nejentsev ()
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Davide Eletto: University of Cambridge
Siobhan O. Burns: University College London Institute of Immunity and Transplantation
Ivan Angulo: University of Cambridge
Vincent Plagnol: University College London Genetics Institute, University College London
Kimberly C. Gilmour: Great Ormond Street Hospital for Children NHS Foundation Trust
Frances Henriquez: Great Ormond Street Hospital for Children NHS Foundation Trust
James Curtis: University of Cambridge
Miguel Gaspar: University of Cambridge
Karolin Nowak: University College London Institute of Child Health
Vanessa Daza-Cajigal: University College London Institute of Immunity and Transplantation
Dinakantha Kumararatne: Addenbrooke’s Hospital
Rainer Doffinger: Addenbrooke’s Hospital
Adrian J. Thrasher: Great Ormond Street Hospital for Children NHS Foundation Trust
Sergey Nejentsev: University of Cambridge

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13992

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