title: Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection.
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.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Davide
authors.initials: D
authors.lastname: Eletto
authors.affiliation: University College London Institute of Immunity and Transplantation, London NW3 2PF, UK.|Department of Immunology, Royal Free London NHS Foundation Trust, London NW3 2PF, UK.
authors.forename: Siobhan O
authors.initials: SO
authors.lastname: Burns
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Angulo
authors.affiliation: University College London Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Vincent
authors.identifier: 0000-0002-5597-9215
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
authors.forename: Frances
authors.initials: F
authors.lastname: Henriquez
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: James
authors.initials: J
authors.lastname: Curtis
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gaspar
authors.affiliation: University College London Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Karolin
authors.initials: K
authors.lastname: Nowak
authors.affiliation: University College London Institute of Immunity and Transplantation, London NW3 2PF, UK.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Daza-Cajigal
authors.affiliation: Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
authors.forename: Dinakantha
authors.initials: D
authors.lastname: Kumararatne
authors.affiliation: Department of Clinical Biochemistry and Immunology, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.|University College London Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Sergey
authors.initials: S
authors.lastname: Nejentsev
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D001773:Blood Cells / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D004198:Disease Susceptibility; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000737:chemistry / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009164:Mycobacterium Infections / Q000201:enzymology* / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation / Q000187:drug effects; D000072417:Protein Domains; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D053634:TYK2 Kinase / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D016898:Interferon-alpha; D050791:STAT Transcription Factors; D007371:Interferon-gamma; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D053634:TYK2 Kinase; C070139:TYK2 protein, human