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Mucosal Immunol. 2018 Mar;11(2):562-574. doi: 10.1038/mi.2017.74. Epub 2017 Nov 1.

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Author information

1
Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
2
Dr von Hauner Children's Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany.
3
University of Adelaide, Adelaide, South Australia, Australia.
4
The Francis Crick Institute, London, UK.
5
The Wellcome Trust Centre for Human Genetics, Oxford, UK.
6
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University, Atlanta, Georgia, USA.
7
Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.
8
Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital London, London, UK.
9
SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
10
Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
11
Department of Paediatrics, University of Oxford, Oxford, UK.
12
NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
13
INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
14
Department of Haematology, University of Cambridge, Cambridge, UK.
15
NHS Blood and Transplant, Cambridge, UK.
16
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
17
NHS Blood and Transplant-Oxford Centre, Oxford, UK.
18
Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
19
Department of Paediatric Gastroenterology, The Royal Hospital for Children, Glasgow, UK.
20
Royal Hospital for Sick Children, Edinburgh, UK.
21
Child Life and Health, University of Edinburgh, Edinburgh, UK.
22
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
23
Centre for Cellular and Molecular Physiology, University of Oxford, Oxford, UK.
24
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
25
Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland.
26
National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.
27
Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
28
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA.
29
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
30
Icahn School of Medicine, Mount Sinai Hospital, New York, New York, USA.
31
Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.

Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

PMID:
29091079
PMCID:
PMC5924597
DOI:
10.1038/mi.2017.74
[Indexed for MEDLINE]
Free PMC Article

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