title: Novel de novo mutations of the interleukin-10 receptor gene lead to infantile onset inflammatory bowel disease.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Cheng Hiang
authors.initials: CH
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Hsu
authors.affiliation: Sydney Medical School Nepean, The University of Sydney, Australia. Electronic address: brigitte.nanan@sydney.edu.au.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Nanan
authors.affiliation: Sydney Medical School Nepean, The University of Sydney, Australia. Electronic address: ralph.nanan@sydney.edu.au.
authors.forename: Ralph
authors.initials: R
authors.lastname: Nanan
authors.affiliation: 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.
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Gaskin
authors.affiliation: Concord Repatriation General Hospital, Sydney, Australia; The University of New South Wales, Sydney, Australia. Electronic address: rupertleong@hotmail.com.
authors.forename: Rupert W
authors.initials: RW
authors.lastname: Leong
authors.affiliation: 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.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murchie
authors.affiliation: 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.
authors.forename: Aleixo M
authors.initials: AM
authors.lastname: Muise
authors.affiliation: The Children's Hospital at Westmead, Sydney, Australia. Electronic address: michael.stormon@health.nsw.gov.au.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Stormon
mesh_terms: D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005091:Exons / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000628:therapy; D016753:Interleukin-10 / Q000378:metabolism; D053709:Interleukin-10 Receptor alpha Subunit / Q000032:analysis / Q000172:deficiency / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000737:chemistry; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018389:Codon, Nonsense; D053709:Interleukin-10 Receptor alpha Subunit; D016753:Interleukin-10
keywords: Interleukin 10 deficiency;; Paediatric; Very early onset inflammatory bowel disease;