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Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

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...

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Autores principales: Eletto, Davide, Burns, Siobhan O., Angulo, Ivan, Plagnol, Vincent, Gilmour, Kimberly C., Henriquez, Frances, Curtis, James, Gaspar, Miguel, Nowak, Karolin, Daza-Cajigal, Vanessa, Kumararatne, Dinakantha, Doffinger, Rainer, Thrasher, Adrian J., Nejentsev, Sergey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5196432/
https://www.ncbi.nlm.nih.gov/pubmed/28008925
http://dx.doi.org/10.1038/ncomms13992
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author Eletto, Davide
Burns, Siobhan O.
Angulo, Ivan
Plagnol, Vincent
Gilmour, Kimberly C.
Henriquez, Frances
Curtis, James
Gaspar, Miguel
Nowak, Karolin
Daza-Cajigal, Vanessa
Kumararatne, Dinakantha
Doffinger, Rainer
Thrasher, Adrian J.
Nejentsev, Sergey
author_facet Eletto, Davide
Burns, Siobhan O.
Angulo, Ivan
Plagnol, Vincent
Gilmour, Kimberly C.
Henriquez, Frances
Curtis, James
Gaspar, Miguel
Nowak, Karolin
Daza-Cajigal, Vanessa
Kumararatne, Dinakantha
Doffinger, Rainer
Thrasher, Adrian J.
Nejentsev, Sergey
author_sort Eletto, Davide
collection PubMed
description 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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spelling pubmed-51964322017-01-09 Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection Eletto, Davide Burns, Siobhan O. Angulo, Ivan Plagnol, Vincent Gilmour, Kimberly C. Henriquez, Frances Curtis, James Gaspar, Miguel Nowak, Karolin Daza-Cajigal, Vanessa Kumararatne, Dinakantha Doffinger, Rainer Thrasher, Adrian J. Nejentsev, Sergey Nat Commun Article 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. Nature Publishing Group 2016-12-23 /pmc/articles/PMC5196432/ /pubmed/28008925 http://dx.doi.org/10.1038/ncomms13992 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Eletto, Davide
Burns, Siobhan O.
Angulo, Ivan
Plagnol, Vincent
Gilmour, Kimberly C.
Henriquez, Frances
Curtis, James
Gaspar, Miguel
Nowak, Karolin
Daza-Cajigal, Vanessa
Kumararatne, Dinakantha
Doffinger, Rainer
Thrasher, Adrian J.
Nejentsev, Sergey
Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection
title Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection
title_full Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection
title_fullStr Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection
title_full_unstemmed Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection
title_short Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection
title_sort biallelic jak1 mutations in immunodeficient patient with mycobacterial infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5196432/
https://www.ncbi.nlm.nih.gov/pubmed/28008925
http://dx.doi.org/10.1038/ncomms13992
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