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Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

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Eletto, D 
Burns, SO 
Angulo, I 
Plagnol, V 
Gilmour, KC 


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.



Alleles, Amino Acid Sequence, Base Sequence, Blood Cells, Child, Child, Preschool, Cytokines, Disease Susceptibility, Female, Fibroblasts, Gene Expression Regulation, Humans, Interferon-alpha, Interferon-gamma, Janus Kinase 1, Male, Mutation, Mycobacterium Infections, Pedigree, Phosphorylation, Protein Domains, STAT Transcription Factors, Signal Transduction, TYK2 Kinase, Young Adult

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Nature Communications

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Nature Publishing Group
Wellcome Trust (095198/Z/10/Z)
Wellcome Trust (095198/Z/10/Z and 090233/Z/09/Z); Higher Education Funding Council for England; Great Ormond Street Hospital Children’s Charity; National Institute for Health Research (NIHR); Great Ormond Street Hospital Biomedical Research Centre; NIHR Cambridge Biomedical Research Centre; Alfonso Martin Escudero Foundation