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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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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. |
format | Online Article Text |
id | pubmed-5196432 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
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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