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  Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2

Lipinski, S., Petersen, B.-S., Barann, M., Piecyk, A., Tran, F., Mayr, G., et al. (2019). Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2. Cold Spring Harbor Molecular Case Studies, 5(1): a002428, 1-19. doi:10.1101/mcs.a002428.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-210A-D Version Permalink: http://hdl.handle.net/21.11116/0000-0003-210B-C
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Cold Spring Harb Mol Case Stud-2019-Lipinski-.pdf (Publisher version), 9MB
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Cold Spring Harb Mol Case Stud-2019-Lipinski-.pdf
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 Creators:
Lipinski, Simone, Author
Petersen, Britt-Sabina, Author
Barann, Matthias, Author
Piecyk, Agnes1, 2, Author              
Tran, Florian, Author
Mayr, Gabriele, Author
Jentzsch, Marlene, Author
Aden, Konrad, Author
Stengel, Stephanie T., Author
Klostermeier, Ulrich C., Author
Sheth, Vrunda, Author
Ellinghaus, David, Author
Rausch, Tobias, Author
Korbel, Jan O., Author
Nothnagel, Michael, Author
Krawczak, Michael, Author
Gilissen, Christian, Author
Veltman, Joris A., Author
Forster, Michael, Author
Forster, Peter, Author
Lee, Clarence C., AuthorFritscher-Ravens, Annette, AuthorSchreiber, Stefan, AuthorFranke, Andre, AuthorRosenstiel, Philip, Author more..
Affiliations:
1IMPRS for Evolutionary Biology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445639              
2Research Group Parasitology, Department Evolutionary Ecology, Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_1445643              

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 Abstract: Whole-genome and whole-exome sequencing of individual patients allow the study of rare and potentially causative genetic variation. In this study, we sequenced DNA of a trio comprising a boy with very-early-onset inflammatory bowel disease (veoIBD) and his unaffected parents. We identified a rare, X-linked missense variant in the NAPDH oxidase NOX1 gene (c.C721T, p.R241C) in heterozygous state in the mother and in hemizygous state in the patient. We discovered that, in addition, the patient was homozygous for a common missense variant in the CYBA gene (c.T214C, p.Y72H). CYBA encodes the p22phox protein, a cofactor for NOX1. Functional assays revealed reduced cellular ROS generation and antibacterial capacity of NOX1 and p22phox variants in intestinal epithelial cells. Moreover, the identified NADPH oxidase complex variants affected NOD2-mediated immune responses, and p22phox was identified as a novel NOD2 interactor. In conclusion, we detected missense variants in a veoIBD patient that disrupt the host response to bacterial challenges and reduce protective innate immune signaling via NOD2. We assume that the patient's individual genetic makeup favored disturbed intestinal mucosal barrier function.

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Language(s): eng - English
 Dates: 2017-11-082018-10-292019-022019-02
 Publication Status: Published in print
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 Rev. Method: -
 Identifiers: DOI: 10.1101/mcs.a002428
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Title: Cold Spring Harbor Molecular Case Studies
  Abbreviation : Cold Spring Harb Mol Case Stud
Source Genre: Journal
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Publ. Info: Cold Spring Harbor, NY : Cold Spring Harbor Laboratory Press
Pages: - Volume / Issue: 5 (1) Sequence Number: a002428 Start / End Page: 1 - 19 Identifier: ISSN: 2373-2873
CoNE: https://pure.mpg.de/cone/journals/resource/2373-2873