Cheng Hiang Lee1, Peter Hsu2, Brigitte Nanan3, Ralph Nanan4, Melanie Wong5, Kevin J Gaskin6, Rupert W Leong7, Ryan Murchie8, Aleixo M Muise9, Michael O Stormon10. 1. The Children's Hospital at Westmead, Sydney, Australia; The James Fairfax Institute of Paediatric Nutrition, The University of Sydney, Australia; The Children's Hospital at Westmead Clinical School, The University of Sydney, Australia. Electronic address: lee.gastro@gmail.com. 2. The Children's Hospital at Westmead, Sydney, Australia; Sydney Medical School Nepean, The University of Sydney, Australia. Electronic address: peter.hsu@health.nsw.gov.au. 3. Sydney Medical School Nepean, The University of Sydney, Australia. Electronic address: brigitte.nanan@sydney.edu.au. 4. Sydney Medical School Nepean, The University of Sydney, Australia. Electronic address: ralph.nanan@sydney.edu.au. 5. The Children's Hospital at Westmead, Sydney, Australia; The Children's Hospital at Westmead Clinical School, The University of Sydney, Australia. Electronic address: melanie.wong@health.nsw.gov.au. 6. The Children's Hospital at Westmead, Sydney, Australia; The James Fairfax Institute of Paediatric Nutrition, The University of Sydney, Australia. Electronic address: kevin.gaskin@health.nsw.gov.au. 7. Concord Repatriation General Hospital, Sydney, Australia; The University of New South Wales, Sydney, Australia. Electronic address: rupertleong@hotmail.com. 8. SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada. Electronic address: ryan.murchie@utoronto.ca. 9. SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, and Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada. Electronic address: aleixo.muise@sickkids.ca. 10. The Children's Hospital at Westmead, Sydney, Australia. Electronic address: michael.stormon@health.nsw.gov.au.
Abstract
BACKGROUND AND AIMS: Defects in the interleukin 10 (IL-10) signalling pathway have been shown to cause very early onset inflammatory bowel disease (IBD). We report a patient with severe infantile-onset IBD with a compound heterozygous IL-10 receptor alpha subunit (IL-10RA) mutation, one of which was paternally-inherited and the other occurring de novo. METHODS: Deep sequencing of IL-10, IL-10RA and IL-10 receptor beta subunit (IL-10RB) were performed. Peripheral blood mononuclear cell (PBMC) surface expression of IL-10RA was analysed by flow cytometry. IL-10 signalling pathway was examined by measuring phosphorylated STAT3 in PBMC cultured in the presence of IL-6 or IL-10. RESULT: We identified a missense mutation in exon 4 of IL-10RA (c.583T>C) in one allele and a nonsense mutation in exon 7 of IL-10RA (c.1368G>T) in the other allele. Neither mutation has been reported previously. The patient has functional IL-10RA deficiency despite normal IL-10RA expression. CONCLUSION: This represents the first case report of a de novo mutation of IL-10RA that is associated with very early onset severe IBD. Therefore, IL-10 pathway defect should be considered in patients with infantile-onset IBD even if the parents are non-consanguineous.
BACKGROUND AND AIMS: Defects in the interleukin 10 (IL-10) signalling pathway have been shown to cause very early onset inflammatory bowel disease (IBD). We report a patient with severe infantile-onset IBD with a compound heterozygous IL-10 receptor alpha subunit (IL-10RA) mutation, one of which was paternally-inherited and the other occurring de novo. METHODS: Deep sequencing of IL-10, IL-10RA and IL-10 receptor beta subunit (IL-10RB) were performed. Peripheral blood mononuclear cell (PBMC) surface expression of IL-10RA was analysed by flow cytometry. IL-10 signalling pathway was examined by measuring phosphorylated STAT3 in PBMC cultured in the presence of IL-6 or IL-10. RESULT: We identified a missense mutation in exon 4 of IL-10RA (c.583T>C) in one allele and a nonsense mutation in exon 7 of IL-10RA (c.1368G>T) in the other allele. Neither mutation has been reported previously. The patient has functional IL-10RA deficiency despite normal IL-10RA expression. CONCLUSION: This represents the first case report of a de novo mutation of IL-10RA that is associated with very early onset severe IBD. Therefore, IL-10 pathway defect should be considered in patients with infantile-onset IBD even if the parents are non-consanguineous.
Authors: Bárbara B Colombo; Victor Fattori; Carla F S Guazelli; Tiago H Zaninelli; Thacyana T Carvalho; Camila R Ferraz; Allan J C Bussmann; Kenji W Ruiz-Miyazawa; Marcela M Baracat; Rúbia Casagrande; Waldiceu A Verri Journal: Inflammation Date: 2018-08 Impact factor: 4.092