title: Synergistic effect of interleukin-10-receptor variants in a case of early-onset ulcerative colitis.
abstract: OBJECTIVE
  To investigated the molecular cause of very early-onset ulcerative colitis (UC) in an 18-mo-old affected child.
  
  
  METHODS
  We analysed the interleukin-10 (IL10) receptor genes at the DNA and RNA level in the proband and his relatives. Beta catenin and tumor necrosis factor-α (TNFα) receptors were analysed in the proteins extracted from peripheral blood cells of the proband, his relatives and familial adenomatous polyposis (FAP) and PTEN hamartoma tumor syndrome (PHTS) patients. Samples were also collected from the proband's inflamed colorectal mucosa and compared to healthy and tumour mucosa collected from a FAP patient and patients affected by sporadic colorectal cancer (CRC). Finally, we examined mesalazine and azathioprine effects on primary fibroblasts stabilised from UC and FAP patients.
  
  
  RESULTS
  Our patient was a compound heterozygote for the IL10RB E47K polymorphism, inherited from his father, and for a novel point mutation within the IL10RA promoter (the -413G->T), inherited from his mother. Beta catenin and tumour necrosis factor α receptors-I (TNFRI) protein were both over-expressed in peripheral blood cells of the proband's relatives more than the proband. However, TNFRII was over-expressed only in the proband. Finally, both TNFα-receptors were shown to be under-expressed in the inflamed colon mucosa and colorectal cancer tissue compared to healthy colon mucosa. Consistent with this observation, mesalazine and azathioprine induced, in primary fibroblasts, IL10RB and TNFRII over-expression and TNFRI and TNFα under-expression. We suggest that β-catenin and TNFRI protein expression in peripheral blood cells could represent molecular markers of sub-clinical disease in apparently healthy relatives of patients with early-onset UC.
  
  
  CONCLUSIONS
  A synergistic effect of several variant alleles of the IL10 receptor genes, inherited in a Mendelian manner, is involved in UC onset in this young child.
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Galatola
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Erasmo
authors.initials: E
authors.lastname: Miele
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Strisciuglio
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Lorella
authors.initials: L
authors.lastname: Paparo
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rega
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Delrio
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Duraturo
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Martinelli
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Giovanni Battista
authors.initials: GB
authors.lastname: Rossi
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Staiano
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Izzo
authors.affiliation: Martina Galatola, Lorella Paparo, Francesca Duraturo, Paola Izzo, Marina De Rosa, Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotecnologie Avanzate, University of Naples "Federico II", 80131 Naples, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: De Rosa
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000276:immunology; D017668:Age of Onset; D000890:Anti-Infective Agents / Q000494:pharmacology; D001379:Azathioprine / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics / Q000276:immunology; D040941:Heredity; D006801:Humans; D007223:Infant; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics* / Q000378:metabolism; D053710:Interleukin-10 Receptor beta Subunit / Q000235:genetics* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D019804:Mesalamine / Q000494:pharmacology; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000097:blood; D051176:beta Catenin / Q000097:blood
chemical_list: D000890:Anti-Infective Agents; D015415:Biomarkers; C495270:CTNNB1 protein, human; D005765:Gastrointestinal Agents; C081846:IL10RB protein, human; D053709:Interleukin-10 Receptor alpha Subunit; D053710:Interleukin-10 Receptor beta Subunit; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506235:TNFRSF1A protein, human; C415902:TNFRSF1B protein, human; D051176:beta Catenin; D019804:Mesalamine; D001379:Azathioprine
keywords: Beta catenin; Inflammatory bowel disease; Interleukin 10 receptors; Tumour necrosis factor α receptors; Ulcerative colitis